Gastroesophageal Reflux Disease and Airway Disease

GASTROESOPHAGEAL REFLUX DISEASE AND AIRWAY DISEASE

GASTROESOPHAGEAL REFLUX DISEASE AND AIRWAY DISEASE Edited by

Mark R. Stein University of South Florida College of Medicine, Tampa, Florida

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LUNG BIOLOGY IN HEALTH AND DISEASE Executive Editor Claude Lenfant Director, National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland

1. Immunologic and Infectious Reactions in the Lung, edited by C. H. Kirkpatrick and H. Y. Reynolds 2. The Biochemical Basis of Pulmonary Function, edited by R. G. Crystal 3. Bioengineering Aspects of the Lung, edited by J. B. West 4. Metabolic Functions of the Lung, edited by Y. S. Bakhle and J. R. Vane 5. Respiratory Defense Mechanisms (in two parts), edited by J. D. Brain, D. F. Proctor, and L. M. Reid 6. Development of the Lung, edited by W. A. Hodson 7. Lung Water and Solute Exchange, edited by N. C. Staub 8. Extrapulmonary Manifestations of Respiratory Disease, edited by E. D. Robin 9. Chronic Obstructive Pulmonary Disease, edited by T. L. Petty 10. Pathogenesis and Therapy of Lung Cancer, edited by C. C. Harris 11. Genetic Determinants of Pulmonary Disease, edited by S. D. Litwin 12. The Lung in the Transition Between Health and Disease, edited by P. T. Macklem and S. Permutt 13. Evolution of Respiratory Processes: A Comparative Approach, edited by S. C. Wood and C. Lenfant 14. Pulmonary Vascular Diseases, edited by K. M. Moser 15. Physiology and Pharmacology of the Airways, edited by J. A. Nadel 16. Diagnostic Techniques in Pulmonary Disease (in two parts), edited by M. A. Sackner 17. Regulation of Breathing (in two parts), edited by T. F. Hornbein 18. Occupational Lung Diseases: Research Approaches and Methods, edited by H. Weill and M. Turner-Warwick 19. Immunopharmacology of the Lung, edited by H. H. Newball 20. Sarcoidosis and Other Granulomatous Diseases of the Lung, edited by B. L. Fanburg 21. Sleep and Breathing, edited by N. A. Saunders and C. E. Sullivan 22. Pneumocystis carinii Pneumonia: Pathogenesis, Diagnosis, and Treatment, edited by L. S. Young 23. Pulmonary Nuclear Medicine: Techniques in Diagnosis of Lung Disease, edited by H. L. Atkins 24. Acute Respiratory Failure, edited by W. M. Zapol and K. J. Falke 25. Gas Mixing and Distribution in the Lung, edited by L. A. Engel and M. Paiva

26. High-Frequency Ventilation in Intensive Care and During Surgery, edited by G. Carlon and W. S. Howland 27. Pulmonary Development: Transition from Intrauterine to Extrauterine Life, edited by G. H. Nelson 28. Chronic Obstructive Pulmonary Disease: Second Edition, edited by T. L. Petty 29. The Thorax (in two parts), edited by C. Roussos and P. T. Macklem 30. The Pleura in Health and Disease, edited by J. Chrétien, J. Bignon, and A. Hirsch 31. Drug Therapy for Asthma: Research and Clinical Practice, edited by J. W. Jenne and S. Murphy 32. Pulmonary Endothelium in Health and Disease, edited by U. S. Ryan 33. The Airways: Neural Control in Health and Disease, edited by M. A. Kaliner and P. J. Barnes 34. Pathophysiology and Treatment of Inhalation Injuries, edited by J. Loke 35. Respiratory Function of the Upper Airway, edited by O. P. Mathew and G. Sant'Ambrogio 36. Chronic Obstructive Pulmonary Disease: A Behavioral Perspective, edited by A. J. McSweeny and I. Grant 37. Biology of Lung Cancer: Diagnosis and Treatment, edited by S. T. Rosen, J. L. Mulshine, F. Cuttitta, and P. G. Abrams 38. Pulmonary Vascular Physiology and Pathophysiology, edited by E. K. Weir and J. T. Reeves 39. Comparative Pulmonary Physiology: Current Concepts, edited by S. C. Wood 40. Respiratory Physiology: An Analytical Approach, edited by H. K. Chang and M. Paiva 41. Lung Cell Biology, edited by D. Massaro 42. Heart–Lung Interactions in Health and Disease, edited by S. M. Scharf and S. S. Cassidy 43. Clinical Epidemiology of Chronic Obstructive Pulmonary Disease, edited by M. J. Hensley and N. A. Saunders 44. Surgical Pathology of Lung Neoplasms, edited by A. M. Marchevsky 45. The Lung in Rheumatic Diseases, edited by G. W. Cannon and G. A. Zimmerman 46. Diagnostic Imaging of the Lung, edited by C. E. Putman 47. Models of Lung Disease: Microscopy and Structural Methods, edited by J. Gil 48. Electron Microscopy of the Lung, edited by D. E. Schraufnagel 49. Asthma: Its Pathology and Treatment, edited by M. A. Kaliner, P. J. Barnes, and C. G. A. Persson 50. Acute Respiratory Failure: Second Edition, edited by W. M. Zapol and F. Lemaire 51. Lung Disease in the Tropics, edited by O. P. Sharma 52. Exercise: Pulmonary Physiology and Pathophysiology, edited by B. J. Whipp and K. Wasserman 53. Developmental Neurobiology of Breathing, edited by G. G. Haddad and J. P. Farber 54. Mediators of Pulmonary Inflammation, edited by M. A. Bray and W. H. Anderson 55. The Airway Epithelium, edited by S. G. Farmer and D. Hay

56. Physiological Adaptations in Vertebrates: Respiration, Circulation, and Metabolism, edited by S. C. Wood, R. E. Weber, A. R. Hargens, and R. W. Millard 57. The Bronchial Circulation, edited by J. Butler 58. Lung Cancer Differentiation: Implications for Diagnosis and Treatment, edited by S. D. Bernal and P. J. Hesketh 59. Pulmonary Complications of Systemic Disease, edited by J. F. Murray 60. Lung Vascular Injury: Molecular and Cellular Response, edited by A. Johnson and T. J. Ferro 61. Cytokines of the Lung, edited by J. Kelley 62. The Mast Cell in Health and Disease, edited by M. A. Kaliner and D. D. Metcalfe 63. Pulmonary Disease in the Elderly Patient, edited by D. A. Mahler 64. Cystic Fibrosis, edited by P. B. Davis 65. Signal Transduction in Lung Cells, edited by J. S. Brody, D. M. Center, and V. A. Tkachuk 66. Tuberculosis: A Comprehensive International Approach, edited by L. B. Reichman and E. S. Hershfield 67. Pharmacology of the Respiratory Tract: Experimental and Clinical Research, edited by K. F. Chung and P. J. Barnes 68. Prevention of Respiratory Diseases, edited by A. Hirsch, M. Goldberg, J.-P. Martin, and R. Masse 69. Pneumocystis carinii Pneumonia: Second Edition, edited by P. D. Walzer 70. Fluid and Solute Transport in the Airspaces of the Lungs, edited by R. M. Effros and H. K. Chang 71. Sleep and Breathing: Second Edition, edited by N. A. Saunders and C. E. Sullivan 72. Airway Secretion: Physiological Bases for the Control of Mucous Hypersecretion, edited by T. Takishima and S. Shimura 73. Sarcoidosis and Other Granulomatous Disorders, edited by D. G. James 74. Epidemiology of Lung Cancer, edited by J. M. Samet 75. Pulmonary Embolism, edited by M. Morpurgo 76. Sports and Exercise Medicine, edited by S. C. Wood and R. C. Roach 77. Endotoxin and the Lungs, edited by K. L. Brigham 78. The Mesothelial Cell and Mesothelioma, edited by M.-C. Jaurand and J. Bignon 79. Regulation of Breathing: Second Edition, edited by J. A. Dempsey and A. I. Pack 80. Pulmonary Fibrosis, edited by S. Hin. Phan and R. S. Thrall 81. Long-Term Oxygen Therapy: Scientific Basis and Clinical Application, edited by W. J. O'Donohue, Jr. 82. Ventral Brainstem Mechanisms and Control of Respiration and Blood Pressure, edited by C. O. Trouth, R. M. Millis, H. F. Kiwull-Schöne, and M. E. Schläfke 83. A History of Breathing Physiology, edited by D. F. Proctor 84. Surfactant Therapy for Lung Disease, edited by B. Robertson and H. W. Taeusch 85. The Thorax: Second Edition, Revised and Expanded (in three parts), edited by C. Roussos

86. Severe Asthma: Pathogenesis and Clinical Management, edited by S. J. Szefler and D. Y. M. Leung 87. Mycobacterium avium–Complex Infection: Progress in Research and Treatment, edited by J. A. Korvick and C. A. Benson 88. Alpha 1–Antitrypsin Deficiency: Biology · Pathogenesis · Clinical Manifestations · Therapy, edited by R. G. Crystal 89. Adhesion Molecules and the Lung, edited by P. A. Ward and J. C. Fantone 90. Respiratory Sensation, edited by L. Adams and A. Guz 91. Pulmonary Rehabilitation, edited by A. P. Fishman 92. Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease, edited by J.-P. Derenne, W. A. Whitelaw, and T. Similowski 93. Environmental Impact on the Airways: From Injury to Repair, edited by J. Chrétien and D. Dusser 94. Inhalation Aerosols: Physical and Biological Basis for Therapy, edited by A. J. Hickey 95. Tissue Oxygen Deprivation: From Molecular to Integrated Function, edited by G. G. Haddad and G. Lister 96. The Genetics of Asthma, edited by S. B. Liggett and D. A. Meyers 97. Inhaled Glucocorticoids in Asthma: Mechanisms and Clinical Actions, edited by R. P. Schleimer, W. W. Busse, and P. M. O’Byrne 98. Nitric Oxide and the Lung, edited by W. M. Zapol and K. D. Bloch 99. Primary Pulmonary Hypertension, edited by L. J. Rubin and S. Rich 100. Lung Growth and Development, edited by J. A. McDonald 101. Parasitic Lung Diseases, edited by A. A. F. Mahmoud 102. Lung Macrophages and Dendritic Cells in Health and Disease, edited by M. F. Lipscomb and S. W. Russell 103. Pulmonary and Cardiac Imaging, edited by C. Chiles and C. E. Putman 104. Gene Therapy for Diseases of the Lung, edited by K. L. Brigham 105. Oxygen, Gene Expression, and Cellular Function, edited by L. Biadasz Clerch and D. J. Massaro 106. Beta2-Agonists in Asthma Treatment, edited by R. Pauwels and P. M. O’Byrne 107. Inhalation Delivery of Therapeutic Peptides and Proteins, edited by A. L. Adjei and P. K. Gupta 108. Asthma in the Elderly, edited by R. A. Barbee and J. W. Bloom 109. Treatment of the Hospitalized Cystic Fibrosis Patient, edited by D. M. Orenstein and R. C. Stern 110. Asthma and Immunological Diseases in Pregnancy and Early Infancy, edited by M. Schatz, R. S. Zeiger, and H. N. Claman 111. Dyspnea, edited by D. A. Mahler 112. Proinflammatory and Antiinflammatory Peptides, edited by S. I. Said 113. Self-Management of Asthma, edited by H. Kotses and A. Harver 114. Eicosanoids, Aspirin, and Asthma, edited by A. Szczeklik, R. J. Gryglewski, and J. R. Vane 115. Fatal Asthma, edited by A. L. Sheffer 116. Pulmonary Edema, edited by M. A. Matthay and D. H. Ingbar 117. Inflammatory Mechanisms in Asthma, edited by S. T. Holgate and W. W. Busse 118. Physiological Basis of Ventilatory Support, edited by J. J. Marini and A. S. Slutsky

119. Human Immunodeficiency Virus and the Lung, edited by M. J. Rosen and J. M. Beck 120. Five-Lipoxygenase Products in Asthma, edited by J. M. Drazen, S.-E. Dahlén, and T. H. Lee 121. Complexity in Structure and Function of the Lung, edited by M. P. Hlastala and H. T. Robertson 122. Biology of Lung Cancer, edited by M. A. Kane and P. A. Bunn, Jr. 123. Rhinitis: Mechanisms and Management, edited by R. M. Naclerio, S. R. Durham, and N. Mygind 124. Lung Tumors: Fundamental Biology and Clinical Management, edited by C. Brambilla and E. Brambilla 125. Interleukin-5: From Molecule to Drug Target for Asthma, edited by C. J. Sanderson 126. Pediatric Asthma, edited by S. Murphy and H. W. Kelly 127. Viral Infections of the Respiratory Tract, edited by R. Dolin and P. F. Wright 128. Air Pollutants and the Respiratory Tract, edited by D. L. Swift and W. M. Foster 129. Gastroesophageal Reflux Disease and Airway Disease, edited by M. R. Stein 130. Exercise-Induced Asthma, edited by E. R. McFadden, Jr. 131. LAM and Other Diseases Characterized by Smooth Muscle Proliferation, edited by J. Moss 132. The Lung at Depth, edited by C. E. G. Lundgren and J. N. Miller 133. Regulation of Sleep and Circadian Rhythms, edited by F. W. Turek and P. C. Zee 134. Anticholinergic Agents in the Upper and Lower Airways, edited by S. L. Spector 135. Control of Breathing in Health and Disease, edited by M. D. Altose and Y. Kawakami 136. Immunotherapy in Asthma, edited by J. Bousquet and H. Yssel 137. Chronic Lung Disease in Early Infancy, edited by R. D. Bland and J. J. Coalson 138. Asthma's Impact on Society: The Social and Economic Burden, edited by K. B. Weiss, A. S. Buist, and S. D. Sullivan 139. New and Exploratory Therapeutic Agents for Asthma, edited by M. Yeadon and Z. Diamant 140. Multimodality Treatment of Lung Cancer, edited by A. T. Skarin 141. Cytokines in Pulmonary Disease: Infection and Inflammation, edited by S. Nelson and T. R. Martin 142. Diagnostic Pulmonary Pathology, edited by P. T. Cagle 143. Particle–Lung Interactions, edited by P. Gehr and J. Heyder 144. Tuberculosis: A Comprehensive International Approach, Second Edition, Revised and Expanded, edited by L. B. Reichman and E. S. Hershfield 145. Combination Therapy for Asthma and Chronic Obstructive Pulmonary Disease, edited by R. J. Martin and M. Kraft 146. Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Disease, edited by T. D. Bradley and J. S. Floras 147. Sleep and Breathing in Children: A Developmental Approach, edited by G. M. Loughlin, J. L. Carroll, and C. L. Marcus

148. Pulmonary and Peripheral Gas Exchange in Health and Disease, edited by J. Roca, R. Rodriguez-Roisen, and P. D. Wagner 149. Lung Surfactants: Basic Science and Clinical Applications, R. H. Notter 150. Nosocomial Pneumonia, edited by W. R. Jarvis 151. Fetal Origins of Cardiovascular and Lung Disease, edited by David J. P. Barker 152. Long-Term Mechanical Ventilation, edited by N. S. Hill 153. Environmental Asthma, edited by R. K. Bush 154. Asthma and Respiratory Infections, edited by D. P. Skoner 155. Airway Remodeling, edited by P. H. Howarth, J. W. Wilson, J. Bousquet, S. Rak, and R. A. Pauwels 156. Genetic Models in Cardiorespiratory Biology, edited by G. G. Haddad and T. Xu 157. Respiratory-Circulatory Interactions in Health and Disease, edited by S. M. Scharf, M. R. Pinsky, and S. Magder 158. Ventilator Management Strategies for Critical Care, edited by N. S. Hill and M. M. Levy 159. Severe Asthma: Pathogenesis and Clinical Management, Second Edition, Revised and Expanded, edited by S. J. Szefler and D. Y. M. Leung 160. Gravity and the Lung: Lessons from Microgravity, edited by G. K. Prisk, M. Paiva, and J. B. West 161. High Altitude: An Exploration of Human Adaptation, edited by T. F. Hornbein and R. B. Schoene 162. Drug Delivery to the Lung, edited by H. Bisgaard, C. O’Callaghan, and G. C. Smaldone 163. Inhaled Steroids in Asthma: Optimizing Effects in the Airways, edited by R. P. Schleimer, P. M. O’Byrne, S. J. Szefler, and R. Brattsand 164. IgE and Anti-IgE Therapy in Asthma and Allergic Disease, edited by R. B. Fick, Jr., and P. M. Jardieu 165. Clinical Management of Chronic Obstructive Pulmonary Disease, edited by T. Similowski, W. A. Whitelaw, and J.-P. Derenne 166. Sleep Apnea: Pathogenesis, Diagnosis, and Treatment, edited by A. I. Pack 167. Biotherapeutic Approaches to Asthma, edited by J. Agosti and A. L. Sheffer 168. Proteoglycans in Lung Disease, edited by H. G. Garg, P. J. Roughley, and C. A. Hales 169. Gene Therapy in Lung Disease, edited by S. M. Albelda 170. Disease Markers in Exhaled Breath, edited by N. Marczin, S. A. Kharitonov, M. H. Yacoub, and P. J. Barnes 171. Sleep-Related Breathing Disorders: Experimental Models and Therapeutic Potential, edited by D. W. Carley and M. Radulovacki 172. Chemokines in the Lung, edited by R. M. Strieter, S. L. Kunkel, and T. J. Standiford 173. Respiratory Control and Disorders in the Newborn, edited by O. P. Mathew 174. The Immunological Basis of Asthma, edited by B. N. Lambrecht, H. C. Hoogsteden, and Z. Diamant

175. Oxygen Sensing: Responses and Adaptation to Hypoxia, edited by S. Lahiri, G. L. Semenza, and N. R. Prabhakar 176. Non-Neoplastic Advanced Lung Disease, edited by J. Maurer

ADDITIONAL VOLUMES IN PREPARATION

Therapeutic Targets in Airway Inflammation, edited by N. T. Eissa and D. Huston Respiratory Infections in Asthma and Allergy, edited by S. Johnston and N. Papadopoulos Acute Respiratory Distress Syndrome, edited by M. A. Matthay Upper and Lower Respiratory Disease, edited by J. Corren, A. Togias, and J. Bousquet Venous Thromboembolism, edited by J. E. Dalen Acute Exacerbations of Chronic Obstructive Pulmonary Disease, edited by N. Siafakas, N. Anthonisen, and D. Georgopolous Lung Volume Reduction Surgery for Emphysema, edited by H. E. Fessler, J. J. Reilly, Jr., and D. J. Sugarbaker

The opinions expressed in these volumes do not necessarily represent the views of the National Institutes of Health.

I could never have completed this volume without the support and sacrifice of my loving wife, Phyllis. The editing assistance of my friend and colleague, Lewis Mark, M.D., and the never-ending attention to details by my office manager, Lynn Towers, were both deeply appreciated.

INTRODUCTION

Often in medicine there is the obvious—and the not-so-obvious. Such is the case with asthma, a complex disease that has many causes: the obvious ones (at least we believe we know some of them!) and the not-so-obvious ones! As pointed out by Dr. Stein in his Preface, the association between gastroesophageal reflux and lung disease has been discussed by many for centuries. Yet, it was not so long ago that a publication entitled, ‘‘Silent Gastroesophageal Reflux: An Important but Little Known Cause of Pulmonary Complications,’’ appeared (1). Of course, one could say that this 1962 work is a bit dated. Indeed, since then we have become much more aware of the importance and prevalence of gastroesophageal reflux. This is evidenced by the following statement taken from John Murray and Jay Nadel (2): ‘‘Over one third of the US population have symptoms of gastroesophageal reflux and it is estimated that 10% of these individuals have respiratory symptoms that may be related to gastroesophageal reflux. This frequency of respiratory symptoms in this group is higher than expected in the general population.’’

Furthermore, Drs. Katz and Castell, the authors of Chapter 3 of this volume, point out that ‘‘GERD is arguably the most common disease seen in clinical practice and may present with a multitude of symptoms.’’ v

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Why did it take so long to recognize the importance of the association between gastroesophageal reflux and asthma? There is no simple answer to this question but, in actuality, the question is neither important nor relevant. The fact remains that even today there is much confusion about the association between gastroesophageal reflux and asthma (and other respiratory disorders): ‘‘The relationship between gastroesophageal reflux and asthma is further confused by the hypothesis that respiratory disease causes gastroesophageal reflux’’ (2).

This volume, edited by Dr. Mark Stein, is a unique contribution to a difficult field and it is a new landmark for the series of monographs, ‘‘Lung Biology in Health and Disease.’’ There is no doubt that physicians will find here the answers to their questions about gastroesophageal reflux and that, as a consequence, many patients will be helped. The contributors are experts in their field, and sharing their extensive experience is a true asset to this volume. The ultimate goal of this series of monographs is to contribute to improvements in health. The current volume exemplifies how this goal is reached. As Executive Editor, I am grateful to Dr. Stein and his contributors for the opportunity to include it in the series. Claude Lenfant, M.D. Bethesda, Maryland References 1. 2.

John Hines Kennedy. Dis Chest 1962; 42:42–45. John Murray and Jay Nadel. Textbook of Respiratory Medicine. Philadelphia: W.B. Saunders, 1994.

PREFACE

Clinical insights often appear to be new but may later be found to have been previously recorded and either ignored or lost. This is certainly true regarding the relationship between gastroesophageal reflux and asthma (and other airway diseases). In the Middle Ages, Maimonides noted that asthma occurred after feasting (1). In the late 1800s, Sir William Osler noted a relationship between large evening meals and worsening nocturnal asthma. He stated that ‘‘attacks may be due to direct irritation of the bronchial mucosa or . . . indirectly, too, by reflex influences from the stomach’’ (2). This wisdom seemed to be lost until 1934, when Bray proposed that late-evening overindulgence caused gastric distention, which led to reflex-mediated bronchoconstriction through the vagus nerve (3). References to gastroesophageal-reflux-induced airway disease began to appear with increasing frequency in the 1960s and 1970s. Data suggesting a high incidence of hiatal hernia and gastroesophageal reflux in intrinsic asthma and in patients with idiopathic pulmonary fibrosis appeared in the 1970s (4,5). This was a stimulus for further research at several centers. In 1975, studies were initiated in Denver to explain the relationship between these two commonly occurring conditions, gastroesophageal reflux and asthma. Clinical observations that gastroesophageal reflux was worsened by theophylline led to a study demonstrating that therapeutic theophylline levels were vii

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associated with a decrease in lower esophageal sphincter pressure (6). Additional studies demonstrated aspiration of gastric contents using an isotope technique (7) and evidence for a vagally mediated reflex that permitted gastroesophageal reflux to trigger bronchospasm in both humans and a dog model (8,9). These initial studies, together with the subsequent work of numerous investigators, have provided a scientific basis for approaching the evaluation and treatment of gastroesophageal-reflux-associated airway disease. In 1976, when a report by Mays suggested that 50% of intrinsic asthmatics had gastroesophageal reflux, many felt the study was biased and the percentage too high (4). None, at the time, would have expected that future studies could show prevalence rates of as high as 80% (see Chap. 6). An ever-increasing body of evidence supports the importance of gastroesophageal reflux disease (GERD) as a significant factor in both upper- and lower-airway diseases. Until now, this information had not been presented in a coordinated volume enabling both primary care providers and specialists to grasp these relationships. This book is designed to fill that void, which is also present in most textbooks on asthma and respiratory diseases. It is intended to serve as an extensive review of all aspects of the subjects and to provide the reader with a better understanding of the clinical approaches to diagnosis and treatment in all age groups. It is unfortunate when patients present with severe laryngeal disease or late severe restrictive lung disease, which might have been prevented had these relationships not been missed. Hopefully, this book will provide enough useful clues to help most clinicians identify these patients earlier. The authors have attempted to weave together broad coverage of these relationships in a format that should permit review of selected clinical topics or the entire subject. Important differences should be noted between the diagnostic approach and treatment recommendations for upper- versus lower-airway diseases. Mark R. Stein References 1. 2. 3. 4. 5.

Maimonides M. Treatise on asthma. In: Munter S, ed. Medical Writings of Moses Maimonides. Philadelphia: Lippincott, 1963. Osler WB. The Principles and Practice of Medicine, 8th ed. New York: D. Appleton, 1912. Bray GW. Recent advances in the treatment of asthma and hayfever. Practitioner 1934; 34:342–348. Mays EE. Intrinsic asthma in adults: association with gastroesophageal reflux. JAMA 1976; 236:2626–2628. Mays EE, Dubois JJ, Hamilton GB. Pulmonary fibrosis associated with tracheobron-

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6.

7.

8. 9.

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chial aspiration. A study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial fibrosis of obscure etiology. Chest 1976; 69:512–515. Stein MR, Towner MG, Weber RW, Mansfield LE, Jacobson KW, McDonnell, JT, Nelson HS. The effect of theophylline on the lower esophageal sphincter pressure. Ann Allergy 1980; 45:238–241. Reich SB, Early WC, Ravin TH, Goodman M, Spector S, Stein MR. Evaluation of gastropulmonary aspiration by a radioactive technique: concise communication. J Nucl Med 1977; 18:1079–1081. Mansfield LE, Stein MR. Gastroesophageal reflux and asthma: a possible reflex mechanism. Ann Allergy 1978; 41:222–226. Mansfield LE, Harneister HH, Spalding HS, Smith NJ, Glob N. The role of the vagus nerve in airway narrowing caused by intraesophageal hydrochloric acid provocation and esophageal distention. Ann Allergy 1981; 47:431–434.

CONTRIBUTORS

Brendan J. Canning, Ph.D. Assistant Professor, Division of Clinical Immunology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland Donald O. Castell, M.D. Kimbel Professor and Chairman, Department of Medicine, Allegheny University Hospitals, Philadelphia, Pennsylvania Steven R. DeMeester, M.D. Assistant Professor, Departments of Surgery and Cardiothoracic Surgery, University of Southern California School of Medicine, Los Angeles, California Tom R. DeMeester, M.D. Professor and Chairman, Department of Surgery, University of Southern California School of Medicine, Los Angeles, California Steven J. Filler, M.S., D.D.S. Professor of Dentistry, Division of Hospital Dentistry, University of Alabama School of Dentistry, Birmingham, Alabama Susan M. Harding, M.D.

Associate Professor of Medicine, Division of Pulxi

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monary, Allergy, and Critical Care Medicine, Department of Internal Medicine, University of Alabama at Birmingham, Birmingham, Alabama Philip O. Katz, M.D. Associate Professor and Vice Chairman, Department of Medicine, Allegheny University Hospitals, Philadelphia, Pennsylvania Mani S. Kavuru, M.D. Director, Pulmonary Function Laboratory, Department of Pulmonary and Critical Care Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio James A. Koufman, M.D. Professor, Department of Ontolaryngology, Wake Forest University School of Medicine, Winston-Salem, North Carolina David A. Lazarchik, D.M.D. Associate Professor of Dentistry, Division of Hospital Dentistry, University of Alabama School of Dentistry, Birmingham, Alabama Lyndon E. Mansfield, M.D. Clinical Professor of Medicine, Texas Tech Medical School; Adjunct Professor of Biology, University of Texas; and Director, El Paso Institute of Medical Research and Development, El Paso, Texas Stephen J. McGeady, M.D. Associate Professor of Pediatrics and Chief of Allergy and Immunology, Department of Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania Curtis J. Mello, M.D. Clinical Assistant Professor, Department of Medicine, Brown University School of Medicine, Providence, Rhode Island Susan R. Orenstein, M.D. Professor of Pediatrics, Division of Pediatric Gastroenterology, University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania Joel E. Richter, M.D. Chairman and Professor of Medicine, Department of Gastroenterology, The Cleveland Clinic Foundation, Cleveland, Ohio Stephen J. Sontag, M.D. Department of Medicine, Veterans Affairs Hospital, Hines, and Associate Professor of Medicine, Loyola University Stritch School of Medicine, Maywood, Illinois Mark R. Stein, M.D. Clinical Assistant Professor of Medicine, Department of Medicine, Division of Allergy, University of South Florida College of Medicine, Tampa, Florida

CONTENTS

Introduction (Claude Lenfant) Preface Contributors 1. Embryologic Origins of the Relationship of GERD and Airway Disease Lyndon E. Mansfield I. II. III. IV. V. VI.

Introduction Comparative Embryology Embryology of the Human Lower Respiratory Tract The Esophagus and Stomach Congenital Abnormalities Summary References

v vii xi

1

1 2 5 13 15 17 17

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2. Inflammation in Asthma: The Role of Nerves and the Potential Influence of Gastroesophageal Reflux Disease Brendan J. Canning I. II. III. IV. V.

Inflammation in Asthma Neurogenic Inflammation Effects of Inflammation on Airway Afferent Nerves Effect of Inflammation on Airway Autonomic Nerves Conclusion References

3. Diagnosis of Gastroesophageal Reflux Disease Philip O. Katz and Donald O. Castell I. II. III. IV. V. VI. VII. VIII. IX. X. XI.

Spectrum of Gastroesophageal Reflux Disease Diagnosis Therapeutic Trials Barium Radiographs Endoscopy Laryngoscopy Esophageal Biopsy Prolonged Ambulatory pH Monitoring Esophageal Manometry Hiatal Hernia Approaching the Patient with GERD-Related Airways Disease References

4. The Otolaryngologic Manifestations of GERD James A. Koufman I. Introduction II. Patterns and Mechanisms of Reflux in Otolaryngology Patients III. Acid and Pepsin IV. Clinical Manifestations V. Diagnosis VI. Treatment VII. Reflux, the Internal Environment, and a New Paradigm of Airway Disease

19

20 24 31 34 39 40

55

55 57 58 59 60 61 61 62 65 65 66 67

69

69 72 74 75 80 81 84

Contents

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VIII. Conclusion References

5. GERD: A Major Factor in Chronic Cough Curtis J. Mello I. II. III. IV. V. VI.

85 85

89

Introduction Pathophysiology Clinical Presentation Diagnosis Treatment Conclusion References

89 92 97 98 103 106 106

6. The Prevalence of GERD in Asthma Stephen J. Sontag

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I. II. III. IV. V. VI. VII. VIII. IX.

Introduction Coexistence Definitions Study Design and Sampling Procedures Prevalence of GERD in Adults with Asthma Prevalence of GERD in Children with Asthma Bronchodilators and GER in Asthmatics Incidence The High Prevalence of GER and the GER/Asthma Theory X. Summary XI. Conclusion References

7. GERD, Airway Disease, and the Mechanisms of Interaction Susan M. Harding I. Pathophysiology of Esophageal Acid–Induced Bronchoconstriction II. Factors That Could Promote GERD in Asthmatics III. Lessons from Clinical Experience with Acid Suppression References

115 119 120 122 123 129 131 134 134 135 135 136

139

140 160 170 173

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8. Medical Treatment of Gastroesophageal Reflux Disease and Airway Disease Mani S. Kavuru and Joel E. Richter I. II. III. IV. V. VI.

Introduction Methodology Issues Medical Treatment Surgical Therapy Proposed Approach to GERD-Associated Asthma Future Directions References

9. Surgical Treatment of Gastroesophageal Reflux Disease with Emphasis on Respiratory Symptoms Steven R. DeMeester and Tom R. DeMeester I. Introduction II. Considerations for Surgical Therapy III. Factors to Consider When Choosing the Proper Antireflux Procedure IV. Types of Antireflux Operations V. Surgical Complications VI. Results of Surgery VII. Summary References 10. GERD and Airways Disease in Children and Adolescents Stephen J. McGeady I. II. III. IV. V.

179

179 180 182 196 200 202 203

209

209 210 219 223 226 229 233 234 237

Introduction Upper Airway Manifestation of GERD GERD and Lower Respiratory Tract Diagnosis of GERD Treatment of GERD References

237 238 244 250 254 260

11. Respiratory Complications of Reflux Disease in Infants Susan R. Orenstein

269

I. Physiology: Infants Versus Older Children and Adults II. Gastroesophageal Reflux Disease in Infants

269 272

Contents III. IV. V. VI. VII.

12.

13.

xvii Vicious Cycles Between Reflux and Respiratory Disease Respiratory Diseases in Infants Diagnosis of Reflux in Infantile Respiratory Disease Therapy of Reflux in Infantile Respiratory Disease Conclusion References

273 274 276 277 279 279

Oral Manifestations of GERD David A. Lazarchik and Steven J. Filler

285

I. II. III. IV. V. VI. VII. VIII.

285 286 287 291 292 297 298 299 300

Introduction Oral Soft Tissue Manifestations Hard Tissue Manifestations Relationship of Dental Erosion to Salivary Parameters Differential Diagnosis of Dental Erosion Prevention of Oral Manifestations Treatment of Oral Manifestations Conclusion References

Odds and Ends and the State of the Art Mark R. Stein I. II. III. IV.

GERD in the Geriatric Patient GERD and Airway Disease During Pregnancy State of the Art Conclusions References

Author Index Subject Index

303

304 314 314 318 318 323 353

1 Embryologic Origins of the Relationship of GERD and Airway Disease

LYNDON E. MANSFIELD Texas Tech Medical School University of Texas El Paso Institute of Medical Research and Development El Paso, Texas

I. Introduction There are important interactions between the esophagus, stomach, and respiratory system that are a part of normal day-to-day living. These are physiologic events that involve coordination of the breathing and swallowing functions through a rich array of neural reflexes. Derangement in any of these three organs can have deleterious effects on one or the other neighboring organ’s functions. The purpose of this chapter on embryology is to remind the reader that these important interactions begin early in human embryogenesis. This review is not an extremely detailed embryologic recounting. The references offered at the chapter’s end are provided for the reader who desires more in-depth information. I have tried to minimize the introduction of special argot, whenever possible. Embryology can become very confusing, especially human embryology, as the organs move and change orientation, which then distorts the segmental arrangement and relationship of the early embryo. Most health care providers understand the anatomic relationship of postembryonic life. Therefore, the text is arranged to focus on individual organ development, as they are in the postuterine pattern, rather than using a time-line approach 1

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Table 1 Time Line Gestation

Respiratory tract

Week 2 Week 3 Week 4 Week 5

Laryngotracheal groove Primary laryngeal bud Division into R ⫹ L mainstem bronchi and upper lower middle divisions Larynx—dilation appears in primary laryngotracheal bud Larynx begins chondrification lung growth Epiglottis present Ciliated cells in trachea, bronchi

Week 6 Week 7 Month 3 Months 4–5 Months 6–7 Months 8–9

Stomach/Esophagus Gut partially separated from yolk sac Esophagus Stomach dilation appears

Esophagus elongates Stomach rotates Acid glands in stomach

Terminal sacs appear Surfactant, alveolus monolayers Surfactant sufficient for ex utero

(Table 1). The reader must keep in mind that while the described organ is developing, other processes are occurring which may influence its ultimate maturation. The most important messages derived from the embryology of the respiratory tract, esophagus, and stomach are: 1. 2.

They all have a common origin from the embryonic foregut, as shown in Figure 1. They have the same pattern of innervation, predominantly through the vagus nerve.

II. Comparative Embryology The lower respiratory tract, the stomach, and the esophagus alter during the evolutionary process in a complex process. A.

Fish

Of all the vertebrates, fish have the most unique respiratory apparatus, as respiratory gas exchange occurs in a liquid media. In fish, a series of branchial (branchia

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3

Figure 1 The human embryo at 4 weeks. The laryngotracheal groove has not yet formed a laryngotracheal bud. The future stomach is present as a small dilation at the caudal end of the foregut.

⫽ Gr., gill) arches and clefts appear just caudal to the future head. Water is pumped over the highly vascular tissue of the branchia by specialized branchial muscles. Gas exchange occurs as water enters through the mouth is pumped over the gills, and exhausted through the gill slits. It is clear the branchia are not the forerunner of lungs in air-breathing animals. This role belongs to an organ called the swim bladder, in which the fish store gas, usually oxygen. The swim bladder controls the buoyancy of the fish. The swim bladder is a simple highly vascularized sac, with an opening into the ventral foregut just cephalad to the esophagus. There are two tissue folds sur-

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rounded by muscle similar to that of the esophagus, which open and close the entrance to the swim bladder. These folds are analogous to the true vocal cords. The swim bladder is modified in the air-breathing lung fish. The esophagus of the fish is a short muscular tube. Both the glottis and the esophagus are enervated by branches of the vagus nerve, which contain both the afferent and visceral motor efferent fibers. The nerve fibers converge in areas of the fish hindbrain. This basic neurologic relationship is retained throughout the evolutionary changes. B.

Amphibians

Amphibians have structures that can really be called a lung. It is a bifid organ and extends from the thoracic cavity into the abdomen. There is a distinct identifiable respiratory passageway. The gill muscles are now pharyngeal muscles, which pump air instead of water into the lungs. Body wall muscles become modified to pump the air out of the lungs. The lung is more highly vascularized and has more septation than the swim bladder. However, it is still simple compared to the lungs of the higher organisms. C.

Reptiles

Reptilian lungs show increasing septation and vascularization. The respiratory passage now consists of clearly demarcated areas of the larynx, trachea, and bronchi. The caudal lung segments still extend into the abdominal cavity. The presence of ribs and sternum allow the body wall muscles to provide a more powerful assist for inhalation and exhalation. The pulmonary parenchyma is denser. It is more vascularized in the thoracic cavity, while the ventral and intra-abdominal lung is more sacular and markedly less vascularized. This thin-walled segment acts as a bellows or like an aspiration bulb. It collapses during exhalation and refills during inhalation. D.

Birds

Birds have a complete separation of the respiratory and bellows function of the lung. The avian lung extends into the abdomen. However, all respiratory gas exchange in birds occurs only in the chest cavity. The abdominal or caudal lung now functions solely as a sacular bellows. As the avian lungs enlarge; the length of the esophagus increases proportionately. E.

Mammals

Mammals achieve their own unique respiratory niche by completing the formation of the diaphragm. Now all of the pulmonary functions, that is, bellows and gas exchange, occur in the pleural cavity. The respiratory passage in mammals

Embryologic Origins of GERD

5

has more differentiation, with a distinctive epiglottis and second protective tissue fold, the false vocal cords. F. Anthropoids and Humans

The bipedal upright mammals, humans and their anthropoid relatives, introduce an entirely new lung schema. In quadrupedal mammals, there are four dorsal and four ventral branches from the mainstem bronchus. In humans there are initially six divisions from the bilateral mainstem bronchi leading to the upper, middle, and lower lobes. On the left side, the heart occupies the space of the middle lobe. The left upper and middle mainstem bronchi fuse so that the bipeds have only five lobes versus the eight lobes of the other mammals. Because of the upright stature and the change in heart position, the bipedal chest cavity is wider in the sagittal plane and narrower ventrodorsally than the chest cavity of the quadrupeds. This form is already present in the newborn, showing that this development is not based on later environmental effects. The azygos lobe, which is large and functional in quadrupeds, disappears in the bipeds or appears as an unconnected vestigial nonfunctioning organ with its own blood supply in up to 1% of humans. The esophageal length of humans has the greatest relative proportion compared to the size of lungs among all the animals. The significant differences in the human relate to the adaptation of a full upright position and bipedal locomotion. Significant organ position shifts occur to accommodate the changes required by gravitational effects in the upright bipedal human. The human situation is further complicated by the fact that almost a third of the human life span is spent in a horizontal position with its own shifting effects on organs. There are effects on organ function with this daily 90 degree change in orientation. Some mechanisms may fail to operate as well in the horizontal plane. III. Embryology of the Human Lower Respiratory Tract A. The Epiglottis and Glottis

The epiglottis and glottis are at their most complex in humans and anthropoids. There are large sequential changes from the simple glottis of the fish, which is a simple short muscular ring around the opening into the swim bladder. The glottal muscle of the fish is similar to that found in the short piscine esophagus. The epiglottis begins as a small prominence, the hypobranchial eminence, just behind the future tongue. By the seventh week the epiglottis is clearly separated from the tongue, which moves forward as the epiglottis moves slightly backward (Fig. 2). During this same period, the two lateral folds appear, which connect to

Figure 2 The complex human epiglottis and glottis develop from a simple entrance into the lower respiratory tract, with the addition of the epiglottis, the arytenoids, and the laryngeal ventricles.

Embryologic Origins of GERD

7

base of the epiglottis. At the distant end, the arytenoid cartilages will develop after the folds are connected. The connecting folds are bent so that laryngeal closure has the characteristic ‘‘T’’ shape. Opening of the larynx and vocal cords occurs when the arytenoids draw backward from the epiglottis. B. The Larynx

The anlage of the human laryngeal apparatus are the two simple movable folds that guard the orifice of the lung in the lungfish. These folds are located in the floor of the pharynx and by opening and closing regulate flow into the piscine lung. In humans, at the fourth week of gestation, the laryngotracheal groove appears in foregut, immediately cephalad of the future esophagus. The laryngotracheal groove folds in on itself to form a bud at the ventral part of the rostral foregut. This first budding will develop into the larynx and trachea with subsequent divisions forming the bronchi and bronchioles. The primary bud elongates to become both the larynx and the trachea (Fig. 3). The true vocal cords initially resemble the glottal folds of the fish but subsequently assume their human form and location. By the sixth or seventh week, the characteristic human superstructure to protect the vocal cords and the opening into the lower respiratory passage is present. Its components are the epiglottis, aryepiglotic folds, false vocal cords, and laryngeal ventricles. This complex supraglottal structure is only found in mammals and not in lower animals. The false vocal cords and the laryngeal ventricles are special

Figure 3 The epiglottis originally develops in the pharynx, and then moves back to join the laryngeal apparatus.

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Mansfield

features of humans and anthropoids. In anthropoid apes, the ventricle may also serve a vocal function. The thyroid cartilage is formed by the skeletal base of the fourth visceral arch. The thyroid cartilage occurs only in the mammals. The sixth visceral arch’s skeletal base divides into a central portion, from which the cricoid cartilage arises, and a dorsal portion, which forms the arytenoids (Fig. 4). The muscles that support the laryngeal apparatus are from the sixth visceral segment. The nerve supply to the larynx is the inferior laryngeal nerve, a branch of the vagus. The cricothyroid membrane and musculature is from the fourth visceral segment. As embryogenesis proceeds, the laryngeal epithelium changes to a stratified form. Stratified epithelium in the larynx is found only in humans and anthropoids. The laryngeal ventricles are formed in the supraglottal cavity, by an invagination above each vocal cord. The ventricular cavities are lined with a mucous membrane, in contrast to the stratified epithelium covering much of the larynx. C.

Development of the Trachea, Bronchi, and Lungs

The trachea is formed from the primary laryngotracheal bud, which elongates and also provides the laryngeal structures. The budding divisions continue into the pleuroperitoneal cavities. The endodermal buds, growing laterally, merge with the surrounding mesenchyme and become the lung with its associated bronchi and bronchioles. From the fifth week, when the second buds enlarge to form the primary or

Figure 4 The cartilages forming the larynx and trachea derive from the second, third, fourth, and sixth visceral arches. In humans, the fifth arch involutes.

Embryologic Origins of GERD

9

main stem bronchi, the budding continues until there are 16 or 17 branchings by the twenty-fourth week of gestation (Fig. 5). The splanchnic mesenchyme provides the cartilage for the bronchi and bronchioles. This mesenchyme is also the source of pulmonary smooth muscle, connective tissue, and capillaries. A layer of visceral pleura covering the lungs is derived from the same mesenchyme. The parietal pleura is formed by the somatic mesoderm of the thoracic cavity body wall. During these changes, lung development can be divided into four stages. The first stage is the pseudoglandular period, the second is the canalicular period, the third is the terminal sac period, and the fourth is the alveolar period. The pseudoglandular period lasts from weeks 5 to 17. During this period the lung histology resembles an exocrine gland. By the seventeenth week, all of the major elements of the adult lung are present, except those involved with respiratory gas exchange. Successful ex utero respiration is not possible.

Figure 5 While the lung buds continue to subdivide, the physical separation of the esophagus is completed. The local mesenchyme provides the tissue and capillary bed of the lung.

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Mansfield

During the canalicular period, which begins between 16 and 17 weeks and continues to week 25, there is a period of increased maturation of the lung. The lumen of the bronchi and bronchioles become larger. There is an inward migration of blood vessels. By 24 weeks each terminal bronchiole divides to form two or more respiratory bronchioles. These are thin-layered sacs in direct apposition to capillaries. At this developmental stage respiration is possible, but the fetal lung is too immature to be viable without medical intervention. There is the beginning of surfactant production by specialized alveolar pneumocytes. During the terminal sac period, from week 24 to birth, more terminal sacs develop. The epithelium of these sacs becomes thinner until they are a simple monolayer. Increased surfactant is released from specialized endodermal epithelial known as type I alveolar pneumocytes. The capillary network continues to grow into the lung from the surrounding mesenchyme. Maturation of type II alveolar cells is critical for successful lung function in postdelivery life. Surfactant is required to facilitate the expansion of the thin terminal sacs. By the time the fetus weighs 1 kg (26–28 weeks of gestation) there are sufficient terminal sacs and alveolar surfactant to permit survival of a prematurely born infant. The alveolar period begins during the last part of fetal development and continues to the age of 7 or 8 years. The number of alveoli increase from about 50 million at birth to 300 million with corresponding increased numbers in the tracheobronchial tree. Respiratory reflexes exist in utero. The fetus makes tidal breathing movements before birth. During the initial breathing efforts after delivery, fluid in the lungs is cleared through three routes; through the nose and mouth from pressure on the thorax during delivery, into the lymphatics, and into pulmonary arteries, veins, and capillaries. D.

The Diaphragm

Mammals are the only animal species in which the entire lung is contained in the chest cavity completely separated from the abdominal organs. The entire lung can participate in respiratory gas exchange. No part of the lung is used for a bellows. Instead the bellows function is extrapulmonary, utilizing changes in the pleural space with the power supplied by chest wall muscles and the diaphragm. The primary origin of the diaphragmatic muscle tissue is the cervical region near the fourth and fifth spinal segments. This is the region served by the phrenic nerve, which innervates the musculature of the diaphragm. The phrenic nerve lengthens and descends with the diaphragm as the lung continues to develop to fill the pleural cavity. The diaphragm becomes the caudad limiting factor of the thoracic cavity. The diaphragm is formed from multiple sources (Fig. 6). The lateral parts of the diaphragm develop from the intrachondral muscles. The sternum contrib-

Figure 6 The diaphragm is a complex organ derived from different sources. Its primary innervation, the phrenic nerve, reflects its original position as the superior transversum behind the embryonic heart in the cervical area.

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Mansfield

utes to the ventrolateral fibers. Ligamentous fibers arising from the spine form the dorsal part of the diaphragm. The septum transversum, which initially separated the cervical pericardial cavity, changes to become the central tendon upon which the heart comes to rest in extrauterine life. The esophageal mesentary contributes to the formation of the diaphragm including the crura. The esophageal crura act as a part of the gastroesophageal sphincter. Part of the septum transversum in its original location was penetrated by the aorta, esophagus, azygos vein, thoracic duct, and inferior and superior vena cava, all of which have developed in the surrounding mesenteries. In the term infant, these same organs now traverse the diaphragm. The mesentery of the foregut incorporates itself into the structures of the posterior mediastinum. In most animals, the anterior part of the rectus abdominus reaches up from the pelvis to the first rib. In humans, the rectus divides into four sections. One part becomes the ventrolateral fibers of the diaphragm. A second division becomes the interchondral muscles of the intercostal. A third section becomes the pectoralis major, minor, and subclavus muscles. The remaining tissue becomes the abdominal rectus. The division of the rectus depends on the growth and descent of the lung into the chest. E.

Vascular System

Early in development, the lungs receive their own blood supply from the dorsal aorta. By the fifth week, connection is made to the sixth aortic arch and the pulmonary arteries (Fig. 7). The pulmonary arteries derive from the paired sixth aortic arches. The proximal part of the left arch becomes the left pulmonary artery, and the distal section involutes. The ductus arteriosus, which shunts blood away from the lung, normally involutes to become the ligamentum artriosum. The capillary networks of the lungs come from the surrounding mesenchyme. F. Nervous System

The vagus nerve is the nerve of the foregut and its derivatives. It is formed from the fusion of the nerves of the fourth and sixth arches. The vagus carries both the visceral afferent and efferents (Fig. 8). The larynx is enervated by the superior laryngeal nerve and the recurrent laryngeal nerves, from the fourth and sixth arch, respectively. The sympathetic nervous system develops from neural crest cells, which migrate to form paired ganglia dorsolateral to the aorta. Ganglia are connected by neurofibers forming the sympathetic trunks. Preganglionic fibers from the spinal lateral horn sympathetic axons move into the ganglia and synapse with the ganglionic neurons to ascend or descend down the trunk. Some of the pregangli-

Embryologic Origins of GERD

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Figure 7 The dorsal aorta provides the blood supply to the future lung for a short time. By the week 4, the branches of the sixth aortic arch take over this function.

onic neurons send fibers that pass through the ganglia directly to become splanchnic nerves to the lungs. The parasympathetic nervous system to the lung begins with fibers from brainstem nuclei. They exit the brainstem with the vagus nerve and synapse with ganglionic neurons near the lung structures. Other nerves are present, which do not use acetylcholine as the neurotransmitter but appear associated with the parasympathetic neurons. These neurons may use nitrogen oxide as their neurotransmitter and are the equivalents of the nonadrenergic noncholinergic nervous system. The pattern of innervation of the lung, esophagus, and stomach is very similar. IV. The Esophagus and Stomach A. The Esophagus

The esophagus develops from the portion of the foregut immediately behind the primitive pharynx and the site of the laryngotracheal bud. It is initially separated from the developing trachea by a simple groove, the laryngotracheal groove. This groove ultimately becomes a septum called the tracheoesophageal septum. Initially the esophagus is short, but it grows rapidly as it descends into the

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Mansfield

Figure 8 The respiratory tract, the esophagus, and the stomach are innervated by visceral and somatic afferents and efferents mainly via the vagus. Sympathetic fibers arise from the paravertebral ganglia of the sympathetic chain, the vagus nerve is really the combined nerve of embryonic arches 4 and 6. The nanc system is presumed to be present, but is not well studied in the embryo.

pleural cavity along with the heart and lungs. The esophagus reaches adult relative proportions compared to the lungs by the seventh week of gestation. The epithelial glands of the esophagus are derived from the primitive endoderm. Striated muscle, which forms muscularis externa of the superior third of the esophagus, arises from the mesenchyme of the caudal branchiopharyngeal splanchnic mesenchyme. The esophagus is enervated by branches of the vagus nerve, which were initially associated with the most caudal brancho-pharyngeal arches. In general, the innervation is similar to that of the lungs or stomach.

Embryologic Origins of GERD

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B. The Stomach

The distal part of the foregut is, at first, a simple tubular structure. A slight dilatation appears about the fourth week of gestation. This dilatation is oriented in the sagittal plane as it grows larger, and it then edges ventrodorsally. Since the dorsal border of the primitive stomach grows faster than its ventral border, this differential growth rate leads to the formation of the greater and lesser curvatures of the stomach. The ventrodorsal arrangement, which was apparent in the early embryo is disrupted as the embryo matures. The stomach rotates clockwise 90 degrees. The rotation moves the lesser curvature of the stomach to the right and the greater curvature to the left. The original left side of the stomach now becomes the ventral surface, and the right becomes the dorsal surface. Before rotation, the entry and exit ports of the stomach are in the same longitudinal plane. After rotating, the antrum is now to the left and inferior. The pyloric region is at the right and somewhat superior. At maturation, the stomach’s long axis transverses the long axis of the body. As a result, the left vagus nerve supplies the anterior wall of the adult stomach, and the right vagus nerve supplies the posterior wall. C. The Vascular System

The vascular supply of the stomach is by the gastro-omental arteries from the celiac division of the descending aorta. D. The Nervous System

As mentioned above, the organs of the foregut—the esophagus, the stomach, and the respiratory tract—are innervated by visceral afferents and efferents of the vagus nerve. There are sympathetic and parasympathetic postganglionic fibers, which derive either from the tissue ganglia or the sympathetic chain. The esophagus and stomach also have a noncholinergic, nonadrenergic nervous system (see Chap. 2). The nervous array of the stomach and esophagus is the same as that found in the lungs.

V.

Congenital Abnormalities

A large number of congenital abnormalities of clinical importance occur during embryogenesis of the lower respiratory tract and esophagus. A laryngeal web results from incomplete recanalization of the larynx at about the tenth week. There is partial obstruction to breathing because of the membranous web at the level of the vocal cords. The occurrence of isolated tracheal stenosis or atresia is quite rare. Most often these abnormalities are associated with tracheoesophageal fistula. An even rarer abnormality is a diverticula of the trachea, which appears

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as a blind bronchus. When associated with lung tissue it forms a small tracheal lobe of the lung. The most frequent combined abnormality is the tracheoesophageal fistula. This abnormality appears in up to 1 of 2500 births. The disorder results from incomplete fusion of the tracheoesophageal folds or incomplete development of the tracheoesophageal septum. There are four recognized forms of tracheoesophageal fistula (Fig. 9): 1.

2. 3. 4.

The most common type involves the upper esophagus ending blindly, while the lower portion of the esophagus joins the trachea near the bifurcation. In a second type, the so-called ‘‘H’’ type, there is a tubular connection between the esophagus and the trachea. A third type has the upper esophagus connecting to the trachea with the lower portion connecting to the stomach, but ending blindly. A fourth type has the upper esophagus entering into the trachea, with the lower esophagus exiting the trachea and connecting to the stomach.

Congenital diaphragmatic hernia occurs in up to one of every 3000 births. There is a posteriolateral defect of the diaphragm, which allows the abdominal contents to migrate into the pleural cavity, usually on the left side. Because of the space taken up by the abdominal organs, the ipsilateral lung is hypoplastic. Early recognition is important as the abnormality can be surgically repaired. When the defect is closed, the hypoplastic lung will usually grow and develop normally. Eventration of the diaphram is a similar disorder which involves defective musculature that balloons into the thoracic cavity. Again the abdominal viscera moves into the chest cavity, inhibiting lung growth. Early recognition and surgical repair usually mean a good prognosis.

Figure 9 The type 1 anomaly, consisting of an atretic upper portion of the esophagus with connection of the lower esophagus to the trachea at the bifurcation, is the most frequent type of tracheoesophageal fistula.

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VI. Summary The lower respiratory tract, the esophagus, and the stomach begin embryonic development as part of the foregut. Because of this, they share similar nervous innervation, most significantly the visceral afferents and efferents of the vagus. These nerves will serve to provide the coordination required of the lungs and upper digestive system in extrauterine life. This intimate relationship continues in the infant and adult. References 1. 2. 3. 4. 5. 6. 7. 8.

Allan FD. Essentials of Human Embryology, 2nd ed. New York: Oxford University Press, 1969. Heisler JC. A Text-Book of Embryology for Students of Medicine. Philadelphia: W.B. Saunders, 1899. Keith A. Human Embryology and Morphology, 5th ed. Baltimore: W. Wood & Co., 1933. Langebartel DA. The Anatomical Primer: An Embryological Explanation of Human Gross Morphology. Baltimore: University Park Press, 1977. Langman J. Medical Embryology, 4th ed. Baltimore: Williams & Wilkins, 1981. Moore KL. Color Atlas of Clinical Embryology. Philadelphia: Saunders, 1994. Moore KL. The Developing Human: Clinically Oriented Embryology, 5th ed. Philadelphia: Saunders, 1993. Patten BM. Patten’s Human Embryology: Elements of Clinical Development. New York: McGraw-Hill, 1976.

2 Inflammation in Asthma The Role of Nerves and the Potential Influence of Gastroesophageal Reflux Disease

Brendan J. Canning The Johns Hopkins Medical Institutions Baltimore, Maryland

The National Institutes of Health of the United States described asthma as ‘‘a chronic inflammatory disorder of the airways . . . [which] causes recurrent episodes of wheezing, breathlessness, chest tightness and cough, particularly at night and/or in the early morning’’ (1). This description reflects a seemingly general consensus among clinicians and basic scientists alike that inflammation is not only a characteristic of the asthmatic airways and lungs, but may be the underlying pathogenesis of the disease. Identifying inflammation as the cause, not just a feature, of asthma has led to the concept that reversing and/or preventing the inflammatory processes of asthma may be the most appropriate therapeutic strategy for treating the chronic disease. This belief is reflected in the increasing advocacy of anti-inflammatory agents such as steroids (2,3), the opposition to continuous use of short-acting beta agonists (4,5), and myriad therapeutic strategies currently in development that have been designed to disrupt the inflammatory processes associated with the airway disease (6,7). It is indisputable that gastroesophageal reflux disease (GERD) can initiate symptoms attributed to inflammation in current definitions of asthma (8). It is also indisputable that treatment, particularly surgical treatment, of an underlying reflux disorder can completely cure asthma in some patients and in others mark19

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edly reduce their dependency on corticosteroids for control of their asthmatic condition (9–14). Does reflux, with its potential for aspiration of gastric contents into the airway spaces and lungs, initiate inflammation characteristic of asthma? Alternatively, is the identity of inflammation as the cause of asthma too rigid to adequately describe the asthmatic syndrome that may have many causes, including reflux and inflammation? These are questions that need to be addressed in future clinical research endeavors. A potential link between reflux and asthmatic inflammation is the nervous system. The nervous system has long been recognized as a key element in inflammatory processes throughout the body (15–18), and asthma has also been attributed to a dysfunction of airway nerves (19). The chest pain (20), coughing (8,21,22), and reflex bronchoconstriction (23–26) associated with reflux provide compelling evidence that the nervous system plays a key role in the pathogenesis of GERD. In this chapter the inflammatory attributes of asthma are reviewed as are the potential roles of nerves and GERD in chronic airway disease. I.

Inflammation in Asthma

In their classic treatise on the pathology of asthma, Huber and Koessler (27) described the inflammation in asthma with its associated vascular engorgement (due to dilation of pulmonary blood vessels), mucosal edema (due to an increase in vascular permeability), and inflammatory cell infiltrates (predominantly eosinophils and mononuclear cells). Subsequent autopsy studies (28,29) and more recent studies utilizing bronchial biopsies (30) and bronchoalveolar lavage (31– 33) confirmed that inflammation, particularly mucosal edema and inflammatory cell infiltration, is a consistently observed feature of asthmatic airways. The inflammation associated with asthma that Huber and Koessler described is now known to be mediated by a variety of proinflammatory autacoids and cytokines (34). These substances act directly on target cells within the airways to induce bronchoconstriction, vasodilatation, plasma extravasation, epithelial damage, and edema. They can also act indirectly by inducing expression of inflammatory cell adhesion molecules and chemoattractants, which are necessary for the selective recruitment and migration of inflammatory cells into the airway walls and spaces. The many cells, autacoids, and cytokines that contribute to this inflammatory process are targets for asthma therapy. Table 1 lists selected proinflammatory cytokines and autacoids associated with asthma, their potential source, and their role in inflammation. Eosinophils are the inflammatory cells most commonly associated with asthma (36). Present in lung tissues from patients who have died during an attack of asthma and in bronchial biopsies and lavages recovered from asthma sufferers, eosinophils produce a variety of mediators that might precipitate the symptoms of the disease. Consistent with the hypothesis that eosinophilia might underlie

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the pathogenesis of asthma, eosinophil numbers or activation indices in biopsies or lavage are correlated with disease severity in both asthmatics and animal models of asthma (31,55,56). Furthermore, therapeutic strategies aimed at preventing airway inflammation (such as corticosteroids) in asthma or specifically designed to suppress eosinophil recruitment and activation in models of asthma markedly improve disease severity, most notably, airways hyperresponsiveness, and the need for bronchodilators (32,56,57). The association of atopy with asthma and the correlation of serum IgE with asthma severity make the mast cell, with its high-affinity receptor for IgE, a likely effector in asthma (34,40,58,59). Allergen-induced bronchospasm elicited in a clinical setting closely resembles an acute exacerbation of chronic asthma, and both conditions are effectively treated by drugs that inhibit the actions or release of mast cell–derived autacoids (38,40). Human lung mast cells may also produce proinflammatory cytokines (60). The ability of mast cell activation to precipitate an inflammatory response that is essentially indistinguishable from that associated with chronic asthma provides further evidence for the potential role of mast cells in asthma but also reveals that mast cell activation may not be a sufficient condition. Many atopic individuals will bronchoconstrict and develop a profound inflammatory response to inhaled allergen and yet have no chronic symptoms of asthma (e.g., recurrent wheezing and cough, airways hyperresponsiveness) (61). Furthermore, IgE-deficient mice still develop airways hyperresponsiveness and eosinophilia following allergen challenge (62). This suggests that factors in addition to atopy (e.g., GERD) and high-affinity IgE receptor activation may be necessary for expression of the asthmatic phenotype. The mononuclear cells of the inflammatory cell infiltrates in asthmatic airways are comprised of both lymphocytes and macrophages (30,34,54,63). These cells produce a wide variety of cytokines that play an essential role in orchestrating the processes of lung defense and inflammation. Given their key role in the inflammatory process, the biology and pathobiology of these cells has become perhaps the most intensely investigated field of asthma research. Particular emphasis has been placed on the CD4⫹ T helper (Th) lymphocyte. Based on their production of cytokines associated with cellular immunity and delayed-type hypersensitivity (e.g., IFN-γ, IL-2) or humoral immunity and allergic inflammatory reactions (e.g., IL-4, IL-13, MIP-1α), murine Th cells can be subclassified into Th1 and Th2 subtypes, respectively (64). It has been postulated that if the Th1 / Th2 classification of lymphocytes is applicable to humans, Th2 lymphocytes might be critical in asthma (63). While evidence against the Th1 /Th2 classification of T lymphocytes in humans has been presented, the hypothesis continues to be invoked as a potential explanation for the development of the asthmatic phenotype (35,65,66). Neutrophils and basophils can also be found in asthmatic airways (30,33). Their presence in biopsies and in bronchoalveolar lavage coupled with the obser-

Eosinophils Nervesd

Endothelium, epithelium Plasma kallikrein, glands Macrophages Macrophages

Major basic protein

Tachykininsc

Endothelins

TNF-α IL-1

Bradykinin

Mast cells, basophils, eosinophils Mast cells, basophils

Cellular sourceb

Cysteinyl-leukotrienes (LTC4, D4, and E4) Histamine

Mediator Bronchoconstriction, plasma extravasation, inflammatory cell recruitment Bronchoconstriction, plasma extravasation, vasodilatation Epithelial damage, cholinergic nerve dysfunction Bronchoconstriction, vasodilatation, plasma extravasation, inflammatory cell recruitment Bronchoconstriction, plasma extravasation Bronchoconstriction and cough, vasodilation, plasma extravasation Inflammatory cell recruitment, activation Inflammatory cell recruitment, activation

Potential role in asthma

54 54

53

51,52

46–50

36,41

34,37,40

34,38,39

Ref.

Table 1 Various Inflammatory Mediators Associated with the Pathogenesis of Asthmaa : Cellular Source and Potential Effects in the Lung

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Th lymphocytes

Epithelium, macrophages Epithelium

IL-5

IL-8

Inflammatory cell recruitment promotes mast cell, lymphocyte development promotes IgE and Th2-type cytokine synthesis Eosinophil, basophil maturation and survival; eosinophil, basophil recruitment and activation Inflammatory cell recruitment and priming, airways hyperresponsiveness Inflammatory cell recruitment and priming 6,34

6,33

7,34,55,56

34,35

a This list is merely representative and not intended to be exhaustive. Extensive reviews on other pro-inflammatory cytokines, chemokines, and autacoids associated with the pathogenesis of asthma can be found elsewhere (6,34–37). b Virtually every cell type in the lung has been implicated as a source of proinflammatory cytokines, chemokines, and autacoids. Cell sources identified above are those most often associated with a specific cytokine and/or autacoid. c Substance P and neurokinin A. d Eosinophils found in inflammatory cell infiltrates are potential sources of substance P (42). Interestingly, monocytes recovered from the lungs of healthy human subjects also contain both substance P messenger RNA and protein (43). This may be a potential source of the substance P found in the lavage and sputum of asthmatics (44,45).

RANTES

Th lymphocytes, basophils

IL-4

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vation that antiasthma therapies inhibit their recruitment and activation in the airways suggests that a potential role for these cells cannot be discounted (57). Indeed, both cell types—particularly the basophil, the only cell other than the mast cell to express the high-affinity IgE receptor—can produce a variety of proinflammatory cytokines (e.g., IL-4, IL-13, MIP-1α) and autacoids (e.g., cysteinyl leukotrienes, histamine) that have been implicated in the pathogenesis of asthma (67) (Table 1). Clinical studies of the association between asthma and GERD have not always distinguished between allergic (atopic or ‘‘extrinsic’’) and nonallergic (nonatopic or ‘‘intrinsic’’) asthma (68–71). Several authors have implied, however, that asthma precipitated by GERD may be more prevalent in patients with no history of atopy (8,12,13). Interestingly, recent studies indicate that chronic airway inflammation in atopic and nonatopic asthmatics does not differ to any great extent (72–76). This suggests that whether the underlying cause of asthma is of intrinsic (e.g., GERD) or extrinsic (e.g., allergen) origin, the resulting pathology is similar. Furthermore, while direct evidence is lacking, these observations also suggest that conditions such as GERD or exercise-induced asthma may precipitate inflammation in susceptible patients. It is unfortunate that airway inflammation has not been assessed in patients with GERD-associated asthma. Such information, particularly before and after effective reflux therapy, might profoundly influence diagnosis of the associated diseases and might also highlight the importance of considering reflux in the diagnosis of asthma. It is possible that patients with GERD-induced asthma may not possess the inflammation characteristic of allergic asthma. Indeed, some asthmatics have little or no evidence of chronic inflammation or peripheral blood eosinophilia (30,36). Alternatively, patients with GERD-associated asthma might have inflamed airways. In severe cases of reflux, patients may aspirate large volumes of gastric contents and, as a consequence, develop potentially fatal acute lung injury (77). Profound inflammation of the lungs has been noted at autopsy in patients expiring from aspiration-induced lung injury (78–80) (see also Chapter 10). In animal models the progression of this disease is dependent upon a cascade of proinflammatory cytokines (TNF-α, IL-8) which induce chemotaxis, endothelial cell adhesion (by inducing expression of endothelial cell adhesion molecules), migration, and activation of neutrophils, which mediate the potentially fatal response (Fig. 1) (78,81–83). It would be interesting to know the effect of reflux therapy on airway inflammation in asthmatic patients who are either responsive or unresponsive to effective treatment of their GERD. II. Neurogenic Inflammation Inflammation is a necessary defense mechanism that serves to protect the body from noxious and infectious insults. The precision of the host response to such

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Figure 1 Effects of acid aspiration on neutrophils and IL-8 recovered by bronchoalveolar lavage (BAL) in a rabbit model of aspiration-induced acute lung injury. (A) Tracheal instillation of acid elicited marked increases in IL-8 recovered (6 hr postinstillation) by BAL. (B) Coincident with the increase in IL-8, the number of neutrophils recovered by BAL also markedly increased, an effect that was accompanied by physiological signs of severe respiratory distress, likely precipitated by acute lung injury. Administering an antibody to IL-8 subsequent to acid instillation reduced IL-8 levels in lavage and prevented neutrophil recruitment and respiratory distress. (Adapted from Ref. 82.)

insults is critical: compromised or insufficient inflammatory responses can have dire, acute consequences, while exaggerated or prolonged inflammatory responses can precipitate chronic disease. Such exaggerated inflammatory responses might precipitate chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, GERD, and asthma. As one of the cardinal signs of the inflammatory process, pain permanently links the nervous system with the sequelae of inflammatory diseases (15–18). The pioneering studies of Bruce (15) and Lewis (16,17) early in this century suggest that neuronal activation might also be the defining event of an inflammatory response. More recent studies suggest that, like their clearly defined role in the skin of both humans and animals, peripheral nerves may also play a role in mediating and/or modulating the inflammatory processes of the viscera (18,84,85). Dysfunction of airway nerves has long been considered an underlying cause of asthma (19,86,87). Only recently, however, has the role of nerves in asthmatic inflammation been considered. Szentivanyi (88) proposed a link between the nervous system and allergic, asthmatic inflammation, speculating that dysfunction of airway adrenergic nerves and adrenoceptors might underlie the pathogenesis of asthma. The hypothesis that autonomic nerves might modulate inflammation in asthma has been reviewed in detail elsewhere (89).

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The most compelling hypothesis for a role of nerves in airway inflammation invokes a role for the axon reflex (47). First described in the skin and eye by Bruce (15) and further characterized by Lewis (16,17) and others (90), axon reflexes involve peripheral stimulation of sensory nerves and subsequent local release of proinflammatory neurotransmitters that mediate vasodilatation, plasma extravasation through leaky vessels, inflammatory cell recruitment, and, coincident with sensory nerve activation, the sensation of pain and prolonged hyperalgesia (Fig. 2). The peripheral effects of these sensory nerves are most likely due to the release of the tachykinins substance P and neurokinin A (18,84,91). These proinflammatory neuropeptides are localized to the central and peripheral nerve terminals of a specific subset of unmyelinated sensory and visceral afferent nerves. The peripheral terminals of these afferent nerves are exquisitely sensitive to a variety of chemical and mechanical stimuli. If stimulated with sufficient intensity, these nerve endings will generate bursts of action potentials coincident with local tachykinin release. Subsequent to conduction of the action potentials to the central nervous system (CNS) and release of tachykinins and other transmitters in the CNS, these nerves initiate a variety of defensive reflexes. The lung and virtually all visceral organs (including the esophagus) in humans and animals are innervated by tachykinin-containing afferent nerves (84,92–95). Placing them in proximity to the luminal targets of inhaled and/or aspirated irritants, such fibers are readily localized to the airway epithelium (92– 94). Upon stimulation, these sensory nerves orchestrate a variety of defensive reflexes that are critical for homeostasis. Failure or dysfunction of airway sensory nerves will increase susceptibility to noxious insults, infection, and consequently disease (48,96–101). One such reflex mediated by the tachykinin-containing sensory nerves is inflammation. Lundberg and Saria (102) were the first to systematically characterize the role of sensory nerves in pulmonary inflammation. Lung challenge with noxious and proinflammatory stimuli (e.g., cigarette smoke, histamine, bradykinin, and mechanical irritation) elicits marked plasma extravasation from the vasculature in the airway mucosa of rats. However, following chemical desensitization of the tachykinin-containing sensory nerves with capsaicin (an unmyelinated afferent nerve-selective neurotoxin), nearly all proinflammatory stimuli delivered to the lung were rendered ineffective at eliciting plasma extravasation. This observation is essentially identical to that described in the human skin and provides compelling evidence that tachykinin-containing sensory nerves may be key effectors of lung inflammation (16–18,47). Neurogenic inflammation is now well characterized in the lungs of rats, mice, and guinea pigs (48,103). A wide variety of stimuli initiate plasma extravasation by activating tachykinin-containing capsaicin-sensitive nerves (Table 2). Key features of their mechanism of action highlight the role of the peripheral axon reflex. The responses are abolished or markedly inhibited by tachykinin receptor antagonists or chemical desensitization of the tachykinin-containing

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Figure 2 Schematic diagram of an afferent nerve–mediated axon reflex. Nociceptive afferent nerves are highly sensitive to a variety of mechanical and chemical stimuli. If activated with sufficient intensity, these nerves will generate action potentials resulting in peripheral release of proinflammatory neurotransmitters such as the tachykinins substance P and neurokinin A. These potent neuropeptides have multiple effects on the vasculature and cells surrounding an inflamed tissue and can either facilitate or directly mediate an inflammatory response.

nerves. They are unaffected by acute vagotomy (and thus proceed independent of central neuronal input). These neurogenic inflammatory responses are mimicked by exogenous tachykinins or electrical, antidromic stimulation of vagal afferent nerves. Other features of neurogenic inflammation described in animals highlight the potentially profound influence the axon reflex might have on the

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Table 2 Stimuli Initiating Neurogenic Inflammation in the Airwaysa Stimulus Allergen Cigarette smoke Bradykinin Intraesophageal acid Intratracheal acid (or gastric contents) Hyperpneab Hypertonic salineb

Effect of tachykinin receptor antagonism

Ref.

Partial inhibition Complete inhibition Partial inhibition Complete inhibition Complete inhibition

48,104 102,105 102,106 107 108

Complete inhibition Complete inhibition

109 110,111

a

All studies carried out in rats and/or guinea pigs. This list is merely representative; many other stimuli initiate neurogenic inflammation in animals (thoroughly reviewed in Ref. 48). b Used as models of exercise-induced asthma.

airways. Thus, in addition to vasodilatation and plasma extravasation, activation of tachykinin-containing afferent nerves innervating the airways elicits increased excitability of airway parasympathetic ganglion neurons (112–117), mucus secretion (118), and bronchospasm (50,119). Neurogenic inflammation in animals is also associated with inflammatory cell adhesion (in postcapillary venules, also the site of plasma leakage) and subsequent migration into airway walls (105,120,121). This effect may be indirectly mediated by the tachykinins interacting with the endothelial cells or, alternatively, may be mediated directly by the tachykinins interacting with the inflammatory cells (49,105). Of particular relevance to GERD and its role in asthma and inflammation, airway instillation of acid or gastric contents initiates capsaicin-sensitive nervemediated inflammation in animals (Fig. 3) (108). In humans, inhalation of acidic solutions such as citric acid is known to elicit a variety of defensive reflexes indicative of sensory nerve stimulation and most likely due to stimulation of capsaicin-sensitive nerves (122). Interestingly, Hamamoto and colleagues (107) have presented evidence that aspiration of refluxate is not a necessary condition for induction of neurogenic inflammation in guinea pigs (Fig. 4). Upon observing that intraesophageal acid elicits neurogenic inflammation in the airways, this group speculated that either an axon reflex may exist between the esophagus and the trachea or a vascular connection between the two organs may carry inflammatory substances from the esophagus to the lung. While both vascular and neuronal projections between these two organs have been described in the guinea pig

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Figure 3 Effects of tracheal mucosal application of 0.1 M HCl on the activity of a capsaicin-sensitive vagal afferent nerve fiber in the guinea pig. Neuronal activity was recorded extracellularly from tracheal afferent fibers as previously described (123). Brief application of 0.5 ml HCl (0.1 M) elicited a marked increase in afferent nerve fiber activity, an increase that persisted long after mucosal pH was restored to baseline.

Figure 4 Effect of intraesophageal acid infusion on plasma extravasation in the guinea pig (A) trachea and (B) mainstem bronchi. Plasma extravasation was quantified by measuring the amount of serum albumin (prelabeled with Evans Blue dye) recovered in the tissues following challenge. Phosphoramidon was administered to prevent metabolism of endogenously released tachykinins. Acid was infused into the esophagus, which was sutured shut adjacent to the pharynx (thus preventing aspiration). Note that intraesophageal acid elicited marked plasma extravasation from the airways, an effect that was completely abolished by depletion of tachykinins with capsaicin. The plasma extravasation was also abolished by an NK1 tachykinin receptor antagonist. (From Ref. 107.)

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(116,124–126), the potential for such communication in humans has not been assessed. Neurogenic inflammation (induced by capsaicin) resulting in mucosal edema, increased vascular permeability, and inflammatory cell influx has been clearly demonstrated in the human upper airway (127,128). Neurogenic inflammation has also been clearly defined in the human skin (95,129). Both responses are mimicked by exogenously administered tachykinins. Does neurogenic inflammation occur in human central and peripheral airways (130)? The answer to this question is unknown, but several lines of evidence argue in favor of such a process. Thus, in humans, tachykinin receptors are present on airway smooth muscle (50,131), blood vessels (Fig. 5), glands (118), airway ganglion neurons (132), and the airway epithelium (133,134). Furthermore, both capsaicin-sensitive and tachykinin-containing nerves are present in human airways (92,135). In clinical studies, both capsaicin and tachykinins elicit bronchospasm (lower airway vascular effects of capsaicin and the tachykinins have not been assessed in a clinical setting) (135–137). In in vitro studies with human airways, both capsaicin and tachykinins induce mucus secretion and enhance excitability of airway

Figure 5 Neurokinin A–induced relaxations of human intrapulmonary arteries (3–5 mm outer diameter). Relaxations were endothelium-dependent and abolished by a combination of cyclooxygenase and NO synthase inhibitors (indicating they are mediated by prostanoids and nitric oxide produced by the endothelium). Similar results were obtained using substance P. Note the effect of the NK1 selective antagonist CP 99994: tachykinin-induced relaxations of human intrapulmonary arteries were competitively antagonized by NK1 receptor antagonists.

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ganglion neurons (118,132). All of these observations suggest that axonal reflexes occur in the human airways. Given the many proinflammatory effects mediated by tachykinins, it is possible that neurogenic inflammation might contribute to the pathogenesis of asthma. In airway biopsies taken from asthmatics, tachykinin receptor expression is greater than that seen in nonasthmatic airways, a condition that is reversed by steroid treatment (138,139). Consistent with the hypothesis that tachykinins are released during inflammatory responses, tachykinin levels are markedly increased in the lavage and sputum of asthmatics and also during acute attacks (44,45). Some investigators have even observed a marked increase in the density of tachykinin-containing nerve fibers in asthmatic airways (140), although this has not been confirmed by other investigators (141,142). Clearly then, the potential role of tachykinins and airway afferent nerves in asthma cannot be readily discounted (Table 3). III. Effects of Inflammation on Airway Afferent Nerves Vasodilatation and plasma extravasation resulting in the redness (‘‘rubor’’), swelling (‘‘tumor’’), and elevated temperature (‘‘calor’’) of inflamed tissues along with inflammatory cell infiltration are signs of inflammation common to all tissues susceptible to inflammatory disorders (15–17,145). In the skin and in other tissues innervated by somatic nerves, other cardinal signs of inflammation are persistent pain (‘‘dolor’’) and hyperalgesia and thus altered physiology (‘‘functio laesa’’) in the tissues proximal to the inflamed area (85,145). It seems likely that the hyperalgesia mediated by somatic afferent nerves and the exag-

Table 3 Tachykinin Receptor–Mediated Regulation of the Airways and Lungs End organ effects

Tachykinin receptors involveda

Vasodilatationb Plasma extravasation Inflammatory cell recruitment and activation Airway smooth muscle contraction Mucus secretion CNS-mediated reflexesc Modulation of parasympathetic neurotransmission

NK1 NK1, NK1, NK2, NK1 NK1, NK3,

a

NK2 NK2 NK1 NK2, NK3 NK1

Ref. 48 48 49,105,121 50,119,131 118 143,144 112–117

Tachykinins mediate their effects by binding to three different neurokinin (NK) receptor subtypes. Tachykinin receptor pharmacology has been reviewed extensively elsewhere (18,46,84,91). b See Figure 5. c For example, sympathetic, parasympathetic reflexes, cough.

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gerated autonomic reflexes mediated by afferent nerves innervating the viscera are physiologically similar phenomena. Hyperalgesia can be precipitated by a heightened excitability of peripheral afferent nerve terminals (146,147), a heightened excitability of the secondary neurons that transform afferent input into sensation and reflex activity (148,149), or an alteration in the type or quantity of transmitters released from the central nerve terminals of the afferent nerves (150). The resulting alteration in neuronal function renders previously innocuous or moderately irritating stimuli noxious and painful, and now able to provoke inappropriate reflexes that impair maintenance of homeostasis (Fig. 6). The parallels between hyperalgesia associated with inflammation and the nonspecific airways hyperreactivity associated with asthma seem obvious. Compelling evidence that the airway afferent nerves in asthmatics are hyperexcitable has been presented. Airways hyperreactivity renders stimuli that are without effect on lung function in normal patients (e.g., distilled water, bradykinin, adenosine, sulfur dioxide, citric acid, hypertonic saline, sodium metabisulfite) provocative. The resulting bronchospasm is generally prevented by

Figure 6 Schematic diagram illustrating potential mechanisms of hyperalgesia.

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pretreatment with muscarinic receptor antagonists such as ipratropium bromide (151–154). This implies that each of these stimuli initiates bronchospasm by initiating a parasympathetic, cholinergic reflex. Inflammation such as that associated with allergies may induce hyperresponsiveness. In the nose, for example, the response elicited by bradykinin in seasonal allergic rhinitics is markedly enhanced in patients who are in season and symptomatic (155,156). Interestingly, a major difference in the responses of the rhinitics in season is the induction of sneezing (clearly indicating an increased neuronal excitability) and a parasympathetic reflex that is not elicited when allergy symptoms and inflammation are not present. Similar results were obtained with nasal challenge using endothelin-1 (157). These data suggest that sensitization of the afferent nerve endings induced by allergen challenge may enhance neuronal excitability. This has been directly demonstrated in the guinea pig airways and in isolated vagal afferent neurons (123,158). Furthermore, capsaicin pretreatment or tachykinin receptor antagonists reverse antigen-induced airways hyperresponsiveness in several species including nonhuman primates (159–163). Inflammation might also alter airway afferent nerve neurotransmitter expression. Fischer and colleagues (164) observed that inhalation challenge of allergic guinea pigs with allergen induced preprotachykinin gene expression in vagal afferent neurons that normally do not produce tachykinins. Coincident with the increase in preprotachykinin gene expression, there was a three- to four-fold increase in airway nerve tachykinin content. A similar effect can be elicited by intratracheal instillation of nerve growth factor (NGF) (165). Interestingly, NGF may be produced by mast cells, and NGF levels in serum from allergic asthmatics are more than 30 times that found in healthy subjects (166). Gastroesophageal reflux disease might induce airways hyperresponsiveness by sensitizing airway afferent nerves. Such an effect might proceed directly through the effects of refluxate contents on the afferent nerve endings or indirectly through the formation of autacoids and cytokines that might subsequently alter afferent nerve excitability. IL-8, for example, which is produced in the lung following aspiration of gastric contents (82) (Fig. 1), is known to induce hyperalgesia in animals (167). Interestingly, IL-8 also induces bronchial hyperresponsiveness in guinea pigs (168). Bradykinin is also formed at sites of plasma leakage such as that elicited by aspiration and is an extremely potent stimulant of airway afferent nerves (53). Endothelins, potent, proinflammatory peptides synthesized by epithelial and endothelial cells known to be produced during mucosal damage in the gastrointestinal tract (169), might also be produced in the airway upon aspiration (51). Endothelins have been reported to have multiple effects on airway nerves (52). Clinical studies indicate that reflux in the absence of aspiration can also increase airways responsiveness (24,170) (see Chap. 7). It seems possible that there is a peripheral neuronal communication between the esophagus and the

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airways. In a study of the relaxant innervation of the guinea pig airways, for example, stimulation of capsaicin-sensitive vagal afferent nerves innervating the esophagus elicited relaxations of airway smooth muscle that were abolished by tachykinin receptor antagonists (116). A series of physiological and pharmacological analyses revealed that these relaxations were mediated by the tachykinins activating, via peripheral reflex, parasympathetic ganglion neurons that innervate the airways but have cell bodies in the esophageal myenteric plexus (which is densely innervated by tachykinin-containing nerves. Indeed, in the guinea pig, per gram of tissue, the esophagus has nearly 10 times the amount of substance P found in the airways) (116,171,172). Subsequent retrograde tracing studies confirmed that esophageal myenteric plexus neurons could be specifically labeled following injection of retrograde neuronal tracer into the airway smooth muscle (Fig. 7) (126). Intraesophageal acid might also increase airways hyperresponsiveness through central mechanisms (Fig. 8). The central terminations of vagal afferent nerves innervating the airways, gastrointestinal tract, heart, and vasculature are distributed in several closely associated brainstem nuclei. Considerable overlap of these central terminations arising from disparate peripheral targets has been noted (175,176). Furthermore, the nuclei containing preganglionic neurons also display marked locational overlap of cell populations projecting axons to different organs (175,176). It seems likely that this lack of precise viscerotopic organization at the level of the CNS might result in alterations in preganglionic nerve activity in one organ elicited by alterations in afferent nerve activity arising from a different organ. Such a scenario might contribute to GERD-associated asthma. Indeed, it is also possible that the converse, namely, alterations in airway afferent nerve activity due to inflammation in asthma, might precipitate reflux through centrally mediated vagal reflexes. Based on such an interaction, it would be interesting to know the relative therapeutic benefit realized by anticholinergic therapy in GERD-associated asthma (153,154).

IV. Effect of Inflammation on Airway Autonomic Nerves The airways are innervated by both sympathetic and parasympathetic nerves (136,137). A frequent error appearing in textbooks is to equate the term parasympathetic with both cholinergic and vagal and the term sympathetic with adrenergic. Using the term vagal to describe the parasympathetic innervation of the airways is clearly inappropriate (as are terms such as vagolytic and vagal blockade) because 70–90% of the vagal nerve fibers projecting to the airways and lungs are afferent fibers that do not specifically subserve parasympathetic reflexes (96). Likewise, the terms cholinergic and adrenergic, originally introduced by Dale (177–179) but not with the intention of replacing the terms parasympathetic and

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Figure 7 Schematic diagram illustrating the arrangement of the parasympathetic ganglia innervating the airways of the guinea pig. Ganglia intrinsic to the airways are labeled immunohistochemically with antisera specific for cholinergic nerves (173). Neither VIP nor NO synthase, putative mediators of noncholinergic parasympathetic nerve-mediated responses in the airway, can be localized to the ganglia intrinsic to the airway wall (125,173). Indeed, only cholinergic responses are elicited when the ganglia intrinsic to the airways are selectively stimulated (124). By contrast, noncholinergic, parasympathetic nerve–mediated responses of the airways can be elicited upon stimulating neurons intrinsic to the esophageal myenteric plexus (124). Recent retrograde tracing and immunohistochemical studies confirm that noncholinergic neurons intrinsic to the esophagus project axons to the adjacent airways (125,126,174). Similar peripheral neuronal projections between the esophagus and the airways in other species including humans have not been assessed.

sympathetic, are also inappropriate for describing the parasympathetic and sympathetic innervation of the airways. Indeed, both parasympathetic and sympathetic nerves contain many transmitters in addition to acetylcholine and noradrenaline, respectively, and it is well established that sympathetic nerves can be cholinergic (180). Accordingly, use of the terms sympathetic and parasympathetic as originally proposed by Langley (181) seems most appropriate. The parasympathetic innervation of the airways plays a dominant role in regulating airway smooth muscle tone and mucus secretion and also regulates airway bronchial vascular tone (118,182–184). Responses mediated by parasympathetic nerve stimulation are both cholinergic and nonadrenergic, noncholiner-

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gic, or NANC in nature (118,182–184). NANC nerve–mediated responses in the airways were first described in preparations of airway smooth muscle (185–187), and their parasympathetic nature was soon described in both guinea pigs (188,189) and cats (190,191). Subsequent studies of airway glandular secretion and vascular tone revealed similar innervation of the glands and vessels of the airways in many species (118,183,184). Immunohistochemical studies carried out in animals and humans have identified a plethora of noncholinergic neurotransmitters in the parasympathetic ganglion neurons innervating the airways, including vasoactive intestinal peptide (VIP) and related peptides (192–196), nitric oxide synthase (NOS) (195–199), calcitonin gene–related peptide (CGRP) (200), substance P (195,201), galanin (202–204), neuropeptide Y (203,205,206), and a host of other putative neurotransmitters that potentially regulate airway caliber, blood flow, and mucus secretion (206–209). Functional studies have confirmed this diversity throughout the airway tree (118,182–184). Parasympathetic, cholinergic responses have also been demonstrated throughout the airway tree (118,182–184). Recent development of an antiserum for choline acetyltransferase, the enzyme that synthesizes acetylcholine and a specific marker for cholinergic nerves, has permitted immunohistochemical studies that confirm the presence of cholinergic nerves throughout the airways (173,210).

Figure 8 Schematic diagram illustrating potential neuronal mechanisms that might precipitate airways hyperresponsiveness. (A) Central mechanisms: airway smooth muscle is innervated by parasympathetic nerves that mediate (cholinergic) contractions and (nonadrenergic, noncholinergic) relaxations. Any stimulus or disease state that increases contractile nerve activity and/or decreases relaxant nerve activity may precipitate bronchospasm and airways hyperresponsiveness. Such stimuli might increase peripheral afferent nerve terminal sensitivity (a), alter neurotransmitter gene expression in primary afferent nerves (b), alter secondary neuronal excitability (c), or alter the excitability of the preganglionic fibers regulating airway caliber (d). Alternatively, vagal afferent nerve activity arising from the esophagus (e) or nonvagal afferent nerve activity (f) arising from tissues not innervated by the vagus nerves (e.g., pharynx, nasal mucosa) might modulate the central pathways regulating airway caliber. (B) Peripheral mechanisms: inflammation might alter autonomic regulation of airway caliber by degrading and/or inactivating relaxant transmitters subsequent to release or altering airway smooth muscle responsiveness to the relaxant neurotransmitters (a) or facilitating release of acetylcholine by interacting with prejunctional receptors on the cholinergic nerve terminals (b). Inflammation might also affect synaptic neurotransmission in the ganglia by modulating the excitability of the parasympathetic ganglion neurons (c) or inducing release of neuromodulatory tachykinins from capsaicin-sensitive vagal afferent nerves that facilitate synaptic neurotransmission. See text for details and references supporting these hypotheses.

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Based on the precedence of studies in other tissues (211) and the observation that both cholinergic and noncholinergic responses can be elicited by vagus nerve stimulation (188,190,191) and can be inhibited with ganglionic blockers such as hexamethonium (189–191), it has been suggested that cholinergic and noncholinergic parasympathetic neurotransmitters are co-released from a single population of postganglionic parasympathetic nerve terminals (212). This hypothesis has not, however, withstood a rigorous test in the guinea pig (124,125,173). Circumstantial and direct immunohistochemical evidence suggests that a similar situation exists in cats (213–215), ferrets (195), and humans (196,216,217). This suggests that while cholinergic and noncholinergic responses might both be mediated by parasympathetic nerves, they may be mediated by anatomically and physiologically distinct populations of nerves and, consequently, may also be regulated in a manner distinct from one another. Surprisingly little is known about the sympathetic innervation of the airways, particularly in humans. Stimulation of adrenergic nerves has been demonstrated to elicit bronchodilatation and prevent bronchospasm in several species (191,218,219). Beta-adrenoceptor antagonists, presumably through their effects on responses mediated by adrenergic nerves and circulating catecholamines, increase bronchial hyperresponsiveness in both humans and animals (89,220,221). The observation that adrenoceptor antagonists are without effect on nerve-mediated responses in isolated human airways has led to the hypothesis that human airway smooth muscle is not innervated by sympathetic nerves (19). Nonadrenergic neurotransmitters have been localized to airway sympathetic nerves, but to date no direct evidence for a functional role of these nerves has been provided (93,222,223). Inflammation can alter airway autonomic nerve activity in the periphery by altering the excitability of the postganglionic autonomic neurons (224), altering synaptic neurotransmission within the autonomic ganglia (225), or altering the release and/or postjunctional effects of the autonomic neurotransmitters (226) (Fig. 8). Parasympathetic nerve-mediated bronchodilation is impaired following acute allergen challenge or in chronically inflamed airways from cats (227) and rabbits (228), respectively. Similarly, mast cell tryptase markedly inhibits relaxation of human airway smooth muscle elicited by the putative NANC relaxant neurotransmitter VIP (229), and several studies have demonstrated profound inhibitory effects of inflammatory cytokines on receptor-mediated relaxations of airway smooth muscle (230). These observations may be of particular relevance to asthma because clinical studies indicate that a failure to dilate with deep inspiration, and not an excessive constriction to contractile agonists, might be the underlying cause of asthmatic airways hyperresponsiveness (231). It has also been suggested that cholinergic neurotransmission might be adversely affected by inflammation (89). Upon release, acetylcholine mediates its effects in the airways by binding with high affinity to muscarinic M3 receptors

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on the postjunctional targets of airway parasympathetic, cholinergic nerves. In addition, however, acetylcholine also activates M2 muscarinic receptors on the prejunctional nerve terminals (232,233). When activated, the prejunctional M2 receptors inhibit acetylcholine release, thereby serving as a brake on the cholinergic nerve terminals during periods of elevated cholinergic nerve activity. Failure of this braking system provided by the prejunctional M2 receptors markedly potentiates the postjunctional effects of parasympathetic, cholinergic nerves (232– 234). Inflammation induced by allergen (41,235), viral infection (236), or ozone exposure (237) can compromise the prejunctional M2 receptor. Circumstantial evidence indicates that a similar dysfunction of the M2 receptors may exist in asthmatics (89). Alternatively, inflammation such as that precipitated by allergen exposure might increase the excitability of airway parasympathetic ganglion neurons (238). Neurogenic inflammation can also alter parasympathetic nerve excitability. Parasympathetic ganglia innervating the airways of humans (92,196), guinea pigs (117,172), ferrets (195), and rats (94) have been shown to be innervated by tachykinin-containing nerve fibers. Exogenously administered tachykinin receptor agonists potentiate responses elicited by parasympathetic nerve stimulation, and indirect evidence indicates that endogenous release of the tachykinins facilitates parasympathetic synaptic neurotransmission(112,113,115). Electrophysiological and pharmacological analyses indicate that the effects of the endogenous tachykinins are mediated by NK3 and NK1 receptors (114,116,172). This is another potential mechanism, namely, peripheral activation of tachykinin-containing nerves that innervate airway ganglia, whereby GERD might alter autonomic tone in the airways.

V.

Conclusion

Inflammation is a hallmark feature of asthma and is likely to precipitate the symptoms and potentially life-threatening exacerbations of the chronic airway disease. Gastroesophageal reflux disease is also a cause of asthma as treatment of an underlying reflux disorder can cure or markedly improve asthma symptoms in some patients. Future clinical studies that assess airway inflammation and its association with GERD and the effects of successful GERD therapy on airway inflammation will greatly enhance our understanding of the relationship between these disorders. Finally, a potential link between airway inflammation and GERD is the nervous system. Nerves are inextricably linked to the pathogenesis of inflammatory diseases, particularly the hyperalgesia that persists long after the initial inflammatory insult. The airways are densely innervated by nerves that might precipitate inflammation and might ultimately account for the airways hyperresponsiveness that is associated with asthma and related disorders. Tachykinins,

40

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which are localized to a specific subset of afferent nerves throughout the body and in the airways of all mammalian species studied including the human, may be key mediators of neurogenic inflammation. Studies carried out in animals confirm the potential role of nerves in airway inflammation, and with the recent development of several potent and selective tachykinin receptor antagonists (46), the potential role of nerves in asthma and airway inflammation in humans may soon be addressed. Acknowledgments The author thanks Mr. K. F. Canning and Ms. B. Hebden for their help in the preparation of this manuscript. The author also acknowledges the assistance of Dr. B. Undem and Dr. R. Kajekar in obtaining the data presented in the figures. This work was made possible by grants from the National Institutes of Health, Bethesda, MD. References 1.

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Canning Sensory neuropeptides are not directly involved in bronchial hyperresponsiveness induced by interleukin-8 in guinea pigs in vivo. Clin Exp Allergy 1996; 26:357– 362. Kurose I, Suematsu M, Miura S, Fukumura D, Serizawa H, Nagata H, Tashiro H, Imaeda H, Tashiro H, Shiozaki H, Suematsu M, Sekizuka E, Tsuchiya M. In vivo mucosal and submucosal microvascular response in the rat stomach during autonomic nervous irritation. In: Yoshikawa M, ed. New Trends in Autonomic Nervous System Research: Basic and Clinical Integration. Amsterdam: Elsevier Science Publishers, 1991:179–183. Wilson NM, Chudry N, Silverman M. Role of the oesophagus in asthma induced by the ingestion of ice and acid. Thorax 1987; 42:506–510. Lundberg JM, Brodin E, Saria A. Effects and distribution of vagal capsaicin-sensitive substance P neurons with special reference to the trachea and lungs. Acta Physiol Scand 1983; 119:243–252. Canning BJ, Fischer A, Undem BJ. Pharmacological analysis of the tachykinin receptors mediating activation of nonadrenergic, noncholinergic relaxant nerves innervating guinea pig trachealis. J Pharmacol Exp Ther 1998; 284:370–377. Canning BJ, Fischer A. Localization of cholinergic nerves in lower airways of guinea pigs using antisera to choline acetyltransferase. Am J Physiol 1997; 272: L731–L738 Moffatt JD. Studies on the nonadrenergic, noncholinergic innervation of airway smooth muscle. Ph.D. dissertation. University of Melbourne, Parkville, Victoria, Australia, 1997. Kalia M, Mesulam MM. Brain stem projections of sensory and motor components of the vagus complex in the cat: I. The cervical vagus and nodose ganglia. J Comp Neurol 1980; 193: 435–465. Kalia M, Mesulam M-M. Brain stem projections of sensory and motor components of the vagus complex in the cat: II. Laryngeal, tracheobronchial pulmonary, cardiac, and gastrointestinal branches. J Comp Neurol 1980; 193:467–508. Dale HH. A survey of present knowledge of the chemical regulation of certain functions by natural constituents of the tissues. Bull Johns Hopkins Hosp 1933; 53:297–347. Dale H. Pharmacology and nerve-endings. Proc R Soc Med 1935; 28:319–332. Dale HH. Symposium on neurohumoral transmission. Pharmacol Rev 1954; 6:1–131. Morris JL, Gibbins IL. Co-transmission and neuromodulation. In: Burnstock G, Hoyle V, eds. Autonomic Neuroeffector Mechanisms. Reading, England: Harwood Academic Publishers, 1992:33–119. Langley JN. The Autonomic Nervous System. Cambridge: W. Heffer & Sons, Ltd., 1921. Canning BJ, Undem BJ. Parasympathetic innervation of airway smooth muscle. In: Raeburn D, Gymbiecz M, eds. Airways Smooth Muscle: Structure Innervation and Neurotransmission. Basel: Birkhauser Verlag AG, 1994:43–77. Coleridge HM, Coleridge JCG. Neural regulation of bronchial blood flow. Respir Physiol 1994; 98:1–13 Matran, R. Neural control of lower airway vasculature—involvement of classical transmitters and neuropeptides. Acta Physiol Scand 1991; (suppl 601):1–54.

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Coburn RF, Tomita T. Evidence for nonadrenergic inhibitory nerves in the guinea pig trachealis muscle. Am J Physiol 1973; 224:1072–1080. Coleman RA, Levy GP. A non-adrenergic inhibitory nervous pathway in guineapig trachea. Br J Pharmacol 1974; 52:167–174. Richardson J, Beland J. Nonadrenergic inhibitory nervous system in human airways. J Appl Physiol 1976; 41:764–771. Chesrown SE, Venugopalan CS, Gold WM, Drazen JM. In vivo demonstration of nonadrenergic inhibitory innervation of the guinea pig trachea. J Clin Invest 1980; 65:314–320. Yip P, Palombini B, Coburn RF. Inhibitory innervation to the guinea pig trachealis muscle. J Appl Physiol 1981; 50:374–382. Irvin CG, Boileau R, Tremblay J, Martin RR, Macklem PT. Bronchodilatation: noncholinergic, nonadrenergic mediation demonstrated in vivo in the cat. Science 1980; 207:791–792. Diamond L, O’Donnell M. A nonadrenergic vagal inhibitory pathway to feline airways. Science 1980; 208:185–188. Dey RD, Shannon WA, Said SI. Localization of VIP-immunoreactive nerves in airways and pulmonary vessels of dogs, cats, and human subjects. Cell Tissue Res 1981; 220:231–238. Laitinen A, Partanen M, Hervonen A, Pelto-Huikko M, Laitinen LA. VIP-like immunoreactive nerves in human respiratory tract. Histochemistry 1985; 82:313–319. Lundberg JM, Fahrenkrug J, Ho¨kfelt T, Martling C-R, Larsson O, Tatemoto K, ¨ nggard A. Co-existence of peptide HI (PHI) and VIP in nerves regulating blood A flow and bronchial smooth muscle tone in various mammals including man. Peptides 1984; 5:593–606. Dey RD, Altemus JB, Rodd A, Mayer B, Said SI, Coburn RF. Neurochemical characterization of intrinsic neurons in ferret tracheal plexus. Am J Respir Cell Mol Biol 1996; 14:207–216. Fischer A, Hoffmann B. Nitric oxide synthase in neurons and nerve fibers of lower airways and in vagal sensory ganglia of man. Am J Respir Crit Care Med 1996; 154:209–216. Kobzik L, Bredt DS, Lowenstein CJ, Drazen J, Gaston B, Sugarbaker D, Stamler JS. Nitric oxide synthase in human and rat lung: Immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol 1993; 9:371–377. Buttery LDK, Springall DR, daCosta FAM, Oliviera H, Hislop AA, Haworth SG, Polak JM. Early abundance of nerves containing NO synthase in the airways of newborn pigs and subsequent decrease with age. Neurosci Lett 1995; 201:219–222. Ward JK, Barnes PJ, Springall DR, Abelli L, Tadjkarimi S, Yacoub MH, Polak JM, Belvisi MB. Distribution of human i-NANC bronchodilator and nitric oxideimmunoreactive nerves. Am J Respir Cell Mol Biol 1995; 13:175–184. Keith IM, Pelto-Huikko M, Schalling M, Ho¨kfelt T. Calcitonin gene-related peptide and its mRNA in pulmonary neuroendocrine cells and ganglia. Histochemistry 1991; 96:311–315. Dey RD, Hoffpauir J, Said SI. Co-localization of vasoactive intestinal peptideand substance P-containing nerves in cat bronchi. Neuroscience 1988; 24:275– 281.

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3 Diagnosis of Gastroesophageal Reflux Disease

PHILIP O. KATZ and DONALD O. CASTELL Allegheny University Hospitals Philadelphia, Pennsylvania

I. Spectrum of Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) is a spectrum of disease that can best be defined as the symptoms and/or signs of esophageal or adjacent organ injury secondary to the reflux of gastric contents into the esophagus or beyond into the oral cavity or airways. The spectrum of symptoms are outlined in Figure 1. Injury is defined based on symptoms or organ damage resulting in esophagitis, laryngeal inflammation, or acute and/or chronic pulmonary injury. Injury to the upper respiratory tract may be caused by direct contact of gastric contents with the mucosal surfaces of the oral cavity, trachea, or lung or by a vagal mediated reflex generated from stimulation of an afferent esophageal receptor resulting in stimulation of the airway. GERD is arguably the most common disease seen in clinical practice and may present with a multitude of symptoms. The typical or classic symptoms are heartburn and regurgitation. Heartburn is substernal burning occurring shortly after meals or upon bending over and is relieved with antacids or other over-thecounter agents. Regurgitation is the spontaneous return of gastric contents into the esophagus or mouth. When present together, these symptoms establish a diagnosis of GERD with greater than 90% certainty. Heartburn is seen daily in 7– 55

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Figure 1 Spectrum of symptom presentation of gastroesophageal reflux disease.

10% of the United States population and at least monthly in about 40–50% (1– 3). A similar prevalence is seen in developed countries throughout the world. Regurgitation is reported weekly by approximately 6% and at least yearly by 45% of the population in one study (2). In this same study, either heartburn or regurgitation was present in 20% of patients surveyed at least weekly and 59% at least monthly. The prevalence of heartburn appears to be inversely associated with increasing age, although the absolute differences are small. Despite the sensitivity and specificity of these two symptoms for the diagnosis of GERD, neither the presence of heartburn and/or regurgitation nor the frequency of these symptoms are predictive of the degree of endoscopic damage to the distal esophagus. Approximately 60% of patients presenting to a physician with typical esophageal symptoms will have erosive esophagitis seen on a diagnostic endoscopic examination; approximately 40% will have a normal endoscopy and will be diagnosed as having nonerosive GERD (4). A number of so-called atypical or extraesophageal symptoms have been associated with GERD, including unexplained substernal chest pain without evidence of coronary artery disease (noncardiac chest pain), asthma, bronchitis, chronic cough, recurrent pneumonia, hoarseness, chronic posterior laryngitis, globus sensation, otalgia, apthous ulcers, hiccups, and erosion of dental enamel. In contrast to heartburn and regurgitation, the prevalence of these atypical or extraesophageal symptoms and their frequency in the general population have not been systematically studied until recently. In a large population-based survey of Caucasians in Olmstead County, Minnesota, designed to assess the prevalence of GERD in the general population (2), unexplained chest pain was seen in 23% of the population yearly and at least weekly in 4%. The frequency of unexplained chest pain surprisingly decreased with age. Forty percent had symptoms for greater than 5 years, and 5% reported severe symptoms. Asthma was reported

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in approximately 9%, bronchitis in approximately 20%, and chronic hoarseness in 15% of patients who had typical GERD symptoms. The association of these atypical symptoms with heartburn and regurgitation is controversial. In the study above one or more atypical symptoms were present in 80% of patients. Atypical symptoms were more common in patients with frequent GERD compared to patients with no GERD symptoms. The only exception was asthma. Heartburn or regurgitation was reported in more than 80% of the patients with unexplained chest pain and in 60% with globus sensation. Approximately 60% of patients with asthma, bronchitis, hoarseness, and pneumonia appeared to have typical symptoms. Other studies of patients with atypical GERD suggest that heartburn and regurgitation are seen less frequently in these patients. Heartburn is reported to be present in 30–50% of patients with hoarseness or asthma and in about half of patients with unexplained chest pain and normal coronary arteries. Hence, the true frequency of GERD in patients with these atypical symptoms is not clear. In prospective studies using endoscopy and ambulatory pH monitoring, between 70 and 80% of asthmatics will have associated GERD (5,6). It has been estimated that 20% of patients with chronic cough will have GERD (7), while as many as 75% of patients with chronic hoarseness referred for pH monitoring will have GERD (8). Despite these high frequencies, this is not necessarily proof of a causeand-effect relationship. Approximately 45% of patients with unexplained chest pain can be shown to have GERD (9). Esophagitis in this population is less likely, being seen in less than 10% (10). Endoscopic esophagitis is seen in 30–40% of patients with asthma (11,12). Esophagitis may progress to severe complications including ulceration, peptic stricture, iron deficiency anemia, and Barrett’s esophagus. Barrett’s esophagus is most important since it is a premalignant condition found in at least 12% of patients with typical symptoms of GERD (4). The condition involves a change from normal squamous epithelial lining to a metaplastic intestinal-type epithelium with typical special stain characteristics. When Barrett’s esophagus is found, periodic follow-up is needed as surveillance for malignancy (see below).

II. Diagnosis A clinical diagnosis of GERD can be reasonably assumed if the symptoms are relieved with a therapeutic trial of antireflux therapy. The diagnosis can be based on diagnostic tests including barium radiographs, esophagoscopy, esophageal motility testing, and/or ambulatory pH monitoring. These tests allow the clinician to demonstrate that reflux occurs and to quantitate it. When used appropriately they identify end-organ effects of reflux on the esophagus and larynx. These tests can also evaluate the effects of reflux on lower esophageal sphincter (LES) pres-

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sure and esophageal acid clearance. Each study will be discussed, pointing out strengths and weaknesses, followed by general guidelines for usage (Table 1). The approach to the patient with suspected airway disease will be discussed separately (see Chap. 7). III. Therapeutic Trials The patient with typical heartburn and regurgitation frequently does not need diagnostic tests to support the diagnosis of GERD. A therapeutic trial of H2antagonists, prokinetic agents, or proton pump inhibitors for 6–8 weeks will often confirm that the symptoms are due to acid reflux. Unfortunately, heartburn is often absent in patients with extraesophageal presentations, including cough, laryngitis, and asthma. When the history for GERD is less reliable, objective diagnostic criteria become more important. Therapeutic trials may be less useful if no symptoms of GERD are present. Clues that airway symptoms may be due to GERD include their onset after meals, onset in a recumbent position, nonseasonal onset, nonallergic onset, absence of other pulmonary pathology, and an increase or precipitation of symptoms after heavy meals or an abundance of alcohol. Patients with chronic cough, normal chest x-ray, lack of response to treatment for postnasal drip, and who are not on angiotensin-converting enzyme inhibitors are likely to have GERD (Chapter 5). Similarly, the failure of response of asthma to bronchodilator therapy should lead the clinician to consider a diagnosis of GERD-related asthma. Patients with reflux laryngitis often complain of morning hoarseness, halitosis, ex-

Table 1 Diagnostic Tests for Gastroesophageal Reflux Disease Categorized According to Specific Questions Being Asked Is abnormal reflux present? Barium upper gastrointestinal series pH monitoring Is there mucosal injury? Barium upper gastrointestinal (air contrast) study Endoscopy Mucosal biopsy Are symptoms due to reflux? pH monitoring (with symptom index) To obtain preoperative information: Esophageal manometry pH monitoring

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cess phlegm, dry mouth, throat clearing, tickle in the throat, closing off of the airways or, if a singer, prolonged warm-up time. Associated chronic sore throat should be sought. Though therapeutic trials are often used in patients with suspected GERD and airways disease, these require higher doses of antireflux therapy for longer periods of time and have not been rigorously tested. Neither cost-effectiveness nor clinical efficacy has been evaluated. Currently, it is our practice as of this writing to use twice the FDA-recommended dose of a proton pump inhibitor divided in twice-daily dosage for a minimum of 8–12 weeks as a therapeutic trial for atypical symptoms.

IV. Barium Radiographs Barium studies are relatively inexpensive and widely available for use in diagnosis of esophageal disease. When evaluating the esophagus, a barium swallow (preferably with double contrast) should be ordered to ensure optimal evaluation. Ordering an upper GI series will often result in insufficient evaluation of esophageal function, concentrate excessively on the stomach and duodenum, and not pay careful attention to potential mucosal or motility abnormalities in the esophagus. The barium swallow is an excellent test to establish the presence of a hiatal hernia; however, up to 60% of the adult population will have a hernia (13), making this a nonspecific finding and not diagnostic of GERD. The presence of free reflux may be seen in up to 30% of normal patients and be absent in up to 60% of patients with proven GERD by pH monitoring (14), making barium an insensitive and nonspecific study to document the presence of reflux. It is often suggested that reflux above the carina or to the thoracic inlet is indicative of the potential for aspiration and is used as an aid in the diagnosis of GERD-associated airway disease. Unfortunately, no prospective or controlled studies have been done to substantiate this anecdotal information. In addition, this finding is usually reported with the patient in the supine position, causing this observation to be even less valid. There has been no association of this so-called ‘‘high’’ reflux on a barium study with the presence of proximal acid exposure on ambulatory pH monitoring (see below). Specific mucosal abnormalities on double contrast barium studies such as thickening of esophageal mucosal folds, erosions, or esophageal ulcers are seen in a minority of patients with GERD leaving this study relatively insensitive for this diagnosis. The diagnosis of Barrett’s esophagus is rarely conclusively made by a barium swallow. The best use of the barium study is in evaluation of suspected complications of GERD, including motility abnormalities or peptic stricture. These abnormalities are predominantly in patients presenting with solid and/or liquid dysphagia. The barium study can identify rings and webs and other obstructive lesions (in-

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cluding carcinoma) that may be associated with dysphagia but are rarely direct complications of GERD. A solid bolus such as a marshmallow or a barium cookie can be given to help localize the site of obstruction in a patient with solid dysphagia. In our opinion, barium swallow should be the first test in evaluation of the patient with dysphagia and should be performed in conjunction with endoscopy in this patient population. Although it may demonstrate that reflux and mucosal injury are occurring, it is rarely of value in establishing a diagnosis of GERD in patients with symptoms other than dysphagia. Few prospective studies have been done with barium swallow in patients with GERD and airway disease, particularly asthma. In children, abnormal studies have been seen in as low as 11% (15) of patients and as high as 100% (16). In adult asthmatics, the sensitivity is usually less than 50%, though hiatal hernia is often present and demonstrable free reflux may be seen in some patients.

V.

Endoscopy

Endoscopy is the single best test to document mucosal abnormalities and establish a diagnosis of erosive esophagitis or Barrett’s esophagus in the patient with suspected gastroesophageal reflux disease. When patients with heartburn and regurgitation are evaluated prospectively, endoscopy reveals erosive esophagitis in 45–60% (4) of patients, with the remainder having nonerosive disease (mucosal edema, hyperemia, or a normal-appearing esophagus). Erosive esophagitis suggests a more serious form of GERD, one that is more likely to require continuous medical therapy or antireflux surgery. Therapy with a proton pump inhibitor (see Chap. 8) for relief and healing is indicated. Barrett’s esophagus can be found in 10–12% (4) of reflux patients undergoing endoscopy. While there are no classic diagnostic features of Barrett’s esophagus, it is most common in Caucasian males over the age of 50. Erosive esophagitis is seen with lower frequency in patients with atypical or extraesophageal symptoms. Although 50% of patients with unexplained chest pain and normal coronary arteries have GERD, the prevalence of erosive esophagitis is 10% or less (10). In GERD-associated asthma, endoscopic esophagitis has been reported in 30–40% (5,6) of adult patients. In one study by Larrain et al. (5) esophagitis was only found in 33% and was predominantly nonerosive. In a study by Sontag and colleagues from the Hines VA in Chicago (6), erosive esophagitis was seen in 39% and Barrett’s esophagus in 12% of patients with asthma and GERD. It is likely that the general population is more typical of the patients described in the former study. There are no absolute indications for endoscopy in the patient with suspected GERD. General guidelines suggest that patients with heartburn who fail to respond to a 6- to 8-week therapeutic trial of pharmacologic therapy, patients who have symptoms for more than 3–5 years, patients over the age of 50, and

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patients with ‘‘alarm’’ symptoms including dysphagia, odynophagia, weight loss, anemia, or Gl bleeding should be considered for endoscopy (17). We believe that white males with GERD should be endoscoped at least once to rule out Barrett’s esophagus. Endoscopic findings may help predict the prognosis and outcome of medical therapy. Patients with erosive esophagitis, particularly Grade 3-4, have a poor response to traditional doses of H2 receptor antagonists and prokinetic agents and often require a proton pump inhibitor for symptom relief and healing. Patients with Grade 2 esophagitis have a variable response to H2 blockers and prokinetics and often require proton pump inhibitors to achieve optimal symptom relief and healing. Recurrence of erosive esophagitis is seen in up to 80% of patients within 3–6 months (18); these patients usually require continuous pharmacologic therapy often with proton pump inhibitors for effective long-term relief. Because they seldom progress to more severe forms of esophagitis, patients with nonerosive esophagitis can be managed with a range of pharmacologic treatments and often respond to on-demand therapy on a long-term basis. It is our opinion that endoscopy is useful for long-term treatment planning in difficult-to-manage cases. Because of the lower frequency of erosive esophagitis, we do not routinely perform endoscopy as our initial study in patients with suspected GERD-related chest pain, asthma, cough, or hoarseness, preferring instead to use ambulatory pH monitoring as our initial diagnostic test (see below). If extraesophageal GERD is confirmed and patients require long-term medical therapy (or antireflux surgery), we perform endoscopy to rule out Barrett’s esophagus. VI. Laryngoscopy Laryngoscopic examination in suspected reflux-related laryngitis reveals edema and erythema of the arytenoid cartilage, posterior larynx and posterior portion of true vocal folds. Diffuse laryngitis may be seen. VII. Esophageal Biopsy Mucosal biopsy and cytology are of limited value in evaluation of the patient with GERD unless Barrett’s esophagus or malignancy is suspected. The light microscopic signs of GERD [elongation of rete pegs and hyperplasia of the basal cell layer (19)] do not distinguish between acute and chronic disease and do not help predict the response to therapy. It is our feeling that these findings are nonspecific and do not aid in the diagnosis of GERD. Microscopic signs of acute esophagitis—polymorphonuclear leukocytes and eosinophils—are present in less than 30% of adult patients with GERD (19) and as such are insensitive diagnostic findings. Biopsy may be more useful in the pediatric population, where higher

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prevalence of PMNs and eosinophils has been reported (20). In today’s costsensitive environment, we do not biopsy the esophagus in patients with GERD unless Barrett’s esophagus is suspected. If the endoscopic appearance is suggestive of Barrett’s esophagus, then a systematic biopsy protocol should be followed to confirm the diagnosis and rule out dysplasia or carcinoma (21). Endoscopic surveillance with biopsies to rule out dysplasia every 1 to 2 years is currently the standard of practice for patients with Barrett’s esophagus. VIII.

Prolonged Ambulatory pH Monitoring

Ambulatory pH monitoring is the best test for quantifying esophageal reflux and determining if symptoms are due to GERD. Now a widely available technology, it is usually performed by placing a 2-mm-diameter catheter transnasally into the esophagus with the distal antimony electrode placed 5 cm above the lower esophageal sphincter, which is located by esophageal manometry (Fig. 2). The probe is connected to a small microcomputer that is worn on a belt or clipped to the waist so that the patient can be monitored in an ambulatory setting. Activity

Figure 2 Placement of pH probe in relation to the lower esophageal sphincter.

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can be tailored to provoke reflux in the setting in which symptoms are normally produced. For example, a patient who has nocturnal asthma after a large meal or after imbibing alcohol can be monitored with instructions to reproduce that clinical situation. A patient with chronic hoarseness who sings professionally will be reminded to sing during the study. Patients with exercise-related symptoms can be studied on a treadmill or while running or weightlifting. Multiple electrodes can be placed simultaneously on a single catheter so that intragastric and intraesophageal pH, distal esophageal and proximal esophageal acid exposure or all three can be monitored simultaneously. This allows demonstration of acid exposure in the proximal esophagus, just below the upper esophageal sphincter (UES), predicting the potential for aspiration in patients with cough, asthma, or hoarseness, in addition to documenting abnormal distal reflux. The intragastric electrode allows monitoring of the gastric acid response to antireflux therapy. Several investigators have placed probes above the upper esophageal sphincter in the hypopharynx (22,23) in order to document reflux above the UES to be more confident of the likelihood of aspiration and/or as the cause of supraesophageal symptoms. With the currently available dual pH probe, the distance between the electrodes is fixed (Fig. 2). By placing the upper electrode above the UES, the lower electrode is no longer 5 cm above the lower esophageal sphincter (LES). This can present problems in data interpretation. Probes placed in the hypopharynx can be somewhat uncomfortable. In addition, normal values are not available and are occasionally subject to interpretation artifact. As there are normal values for distal reflux at 5 cm above the LES and for proximal reflux 20 cm above the sphincter, we believe this is a more useful standard (see Chap. 5) (24,25). Normal values vary slightly between laboratories and are included with reports from the laboratory performing the procedure. In general, the normal time (esophageal pH ⬍ 4) upright is ⱕ6% and supine ⱕ1.2% in the distal esophagus, and the normal time is ⱕ1.1% upright and 0% supine proximally. If the problems mentioned above can be resolved, placement above the UES would be ideal. The microcomputer (data logger) is equipped with a symptom button that allows one to record up to six symptoms during a single study. The patient is instructed to push the appropriate symptom button as well as to record the symptom on a diary card. This allows correlation of reflux events with symptoms, which is especially valuable in patients with extraesophageal symptoms such as asthma, cough, and chest pain and allows correlation between heartburn and reflux in patients who have continued symptoms on medical therapy. Patients with typical symptoms of GERD benefit from pH monitoring to establish a diagnosis when symptoms have failed to respond to a therapeutic trial of pharmacologic therapy and endoscopy does not reveal erosive esophagitis or Barrett’s esophagus. In this case, a single-channel pH probe can be placed with the distal probe 5 cm above the LES. Symptoms can then be correlated with

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reflux and reflux frequency assessed. Patients with known GERD who have heartburn and regurgitation not responding to medical therapy can be monitored while still on therapy with a dual channel intragastric and distal esophageal probe to assess the adequacy of gastric acid suppression and esophageal reflux frequency and to correlate symptoms with reflux events. Patients with continued esophageal acid exposure and or symptoms may require additional therapy. Patients with asthma, cough, or other upper airway symptoms suggestive of GERD are the ideal candidates for ambulatory pH monitoring. It is our practice to perform monitoring early in the patient encounter to establish a diagnosis and symptom correlation where possible. It is also our practice to perform dual channel monitoring with one electrode 5 cm above the LES and a second probe 20 cm above in the proximal esophagus just below the UES (Fig. 2). The presence of abnormal distal esophageal acid exposure can be documented, establishing a diagnosis of GERD. More importantly, the presence of abnormal proximal reflux can be documented, suggesting the potential for aspiration and the greater probability that the extraesophageal symptom is due to GERD. If symptom correlation can be found, this will clinch the diagnosis. The presence of proximal reflux appears to predict the response to medical therapy in patients with pulmonary disease (26,27). Most importantly, a small percentage of patients will have normal distal esophageal acid exposure but demonstrable increased frequency of proximal reflux or reflux into the hypopharynx establishing a diagnosis of GERD. In one study of 10 patients with reflux laryngitis, 3 (30%) demonstrated hypopharyngeal reflux with normal distal acid exposure (22). In a larger, retrospective series, 12% of patients reviewed had only abnormal proximal reflux (26). This group would have been diagnosed incorrectly as normal had only a single-channel study been performed. Studies in adults demonstrate abnormal amounts of acid reflux in up to 70–80% of patients with asthma whether on or off bronchodilator therapy (6). Abnormal acid exposure has been documented in both the upright and supine periods. Ambulatory monitoring is especially useful in establishing symptom correlation but results have been variable. In one study, only 50% of wheezing episodes were found to have any relationship to acid reflux (28). A final diagnosis of reflux-related asthma or cough cannot be firmly established until the symptom responds to a therapeutic intervention. For patients with airways disease, ambulatory monitoring can be particularly valuable in assessing response to therapy, particularly in the patient who has failed to respond to a therapeutic trial. It is our practice to monitor intragastric, distal esophageal, and proximal esophageal pH in this population. Adequacy of intragastric acid suppression can be assessed, as can the presence of esophageal acid exposure and correlation between reflux events and symptoms established. Though the precise timing between a reflux event and symptoms that establish

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causality has not been determined, we believe that if symptoms occur within 5 minutes after a reflux episode, a strong correlation between symptoms and acid exposure can be inferred. IX. Esophageal Manometry Esophageal manometry is useful to establish abnormality of LES pressure or esophageal motility and to obtain preoperative information for the surgeon. Decreased lower esophageal sphincter pressure is a major determinant of gastroesophageal reflux, but a single measurement of LES pressure is rarely low in patients with GERD. In studies from our laboratory, only 4% of patients with gastroesophageal reflux disease had a low LES pressure (29). Esophageal motility abnormalities are found more frequently. The most common finding appears to be ineffective esophageal motility (amplitude of contraction in the distal esophagus less than 30 mmHg occurring with 30% or more of water swallows). In our experience, this is the most common abnormality in patients with GERD, seen in approximately 35% (29). These abnormalities appear to occur with similar frequency in patients with GERD-related asthma and cough. In general, we reserve esophageal manometry for the patient in whom antireflux surgery is being planned to establish the presence or absence of ineffective motility. Patients with asthma and other airways disease have a poor response to antireflux surgery when motility abnormalities are present compared to patients with normal motility. In addition, surgeons can be guided in their choice of antireflux surgery, usually performing a Nissen fundoplication (360 degree wrap) in patients with normal peristalsis and a Toupet procedure (240 degree wrap) in patients with peristaltic abnormalities (see Chap. 7). X.

Hiatal Hernia

Once considered of major importance in causing reflux, hiatal hernia is not predictive of reflux as a cause of the patients’ symptoms. Up to 60% of patients over the age of 60 will have a hiatal hernia when barium radiographs are performed. One study suggested that only 9% of patients with a radiographically demonstrated hernia will actually have typical reflux symptoms (30). Hernias do change the relationship of the LES and crural diaphragm. The LES is displaced above the diaphragm. The low pressure in the hernia can act as a reservoir for acid, allowing earlier reflux during LES relaxations. This may also delay esophageal clearance (31). Patients with large hernias who also have low LES pressure may be more prone to reflux (32), particularly if changes occur that increase intra-abdominal pressure.

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If a patient with suspected airways disease is seen, the following approach is suggested (Fig. 3). A thorough history, physical examination, chest x-ray, and direct laryngoscopy should be performed. If dysphagia is present, a barium swallow should be ordered to rule out esophageal obstruction or obvious motility abnormalities. When ambulatory pH monitoring is available, this is the initial diagnostic procedure of choice and should be performed (Fig. 2). An increase in the percent of time esophageal pH ⬍ 4 compared to normals in either the distal or proximal esophagus should be considered abnormal. If symptoms are present, correlation with reflux events greater than 50% (33) should be considered a positive association. When there is a strong history of heartburn and regurgitation or other previous documentation of GERD and if pH monitoring is not available, a therapeutic trial of antireflux therapy can be attempted. A proton pump inhibitor (omeprazole 20 mg or lansoprazole 30 mg) twice daily for 8–12 weeks is indicated (34). If the patient does not improve, pH monitoring should be performed while therapy is continued. A dual-channel probe with intragastric and distal esophageal electrodes should be placed to ascertain adequate gastric acid suppression and to

Figure 3 Suggested approach to the patient with GERD and airways disease.

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assess the presence of esophageal acid exposure. Symptoms should be correlated with reflux events. If distal esophageal acid exposure is seen more than 1.2% of the time, we would consider this abnormal and would give additional medical therapy. The absence of esophageal acid exposure and adequate gastric acid suppression (pH ⬎ 4, 50% of total time) suggests adequate medical therapy, and an alternative diagnosis should be pursued. Finally, if GERD-associated airways disease is documented, we will endoscope the patient to rule out Barrett’s esophagus prior to instituting long-term medical therapy or considering surgery. References 1. 2.

3. 4.

5. 6. 7.

8. 9.

10. 11. 12. 13. 14. 15.

A Gallup Survey on Heartburn Across America. The Gallup Organization, Inc., 1968. Locke GR, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmstead County, Minnesota. Gastroenterology 1997; 112:5–12. Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Dig Dis Sci 1976; 21:953–956. Winters C, Spurling TJ, Chobanian SJ, et al. Barrett’s esophagus: a prevalent, occult complication of gastroesophageal reflux disease. Gastroenterology 1987; 92:118– 123. Harding SM, Guzzo MR, Richter JE. Prevalence of GERD in asthmatics without reflux symptoms. Gastroenterology 1997; 4:A141. Sontag SJ, O’Connell S, Khandelwal S, et al. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990; 99:613–618. Irwin RS, Corrao WM, Pratter MR. Chronic persistent cough in the adult: The spectrum and frequency of causes and successful outcome of specific therapy. Am Rev Respir Dis 1981; 123:413–422. Weiner GJ, Kaufman JA, Wu WC, et al. Chronic hoarseness secondary to gastroesophageal reflux disease. Am J Gastroenterol 1989; 84:1503–1508. Hewson EG, Sinclair JW, Dalton CB, et al. 24 hour esophageal pH monitoring: the most useful test for evaluating non-cardiac chest pain. Am J Med 1991; 90:576– 583. Cherian P, Smith LF, Bardham KD, Thorpe J, Oakley GD, Dawson D. Esophageal tests in the evaluation of non-cardiac chest pain. Dis Esophagus 1995; 8:129–133. Larrain A, Carrasco E, Galleguillos F, et al. Medical and surgical treatment of nonallergic asthma associated with gastroesophageal reflux. Chest 1991; 99:1330–1336. Sontag SJ, Schnell TG, Miller TQ, et al. Prevalence of oesophagitis in asthmatics. Gut 33:872–76, 1992. Ott DJ, Wu WC, Gelfand DW. Reflux esophagitis revisited: prospective analysis of radiologic accuracy. Gastrointest Radiol 1981; 6:1–7. Richter JE, Castell DO. Gastroesophageal reflux. Pathogenesis, diagnosis, and therapy. Ann intern Med 1982; 97:93–103. Euler AR, Burne WJ, Ament ME, et al. Recurrent pulmonary disease in children: A complication of gastroesophageal reflux. J Pediatr 1984; 87:872–878.

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16.

Herbst JJ, Minton SD, Brooks LS. Gastroesophageal reflux causing respiratory distress and apnea in newborn infants. J Pediatr 1979; 95:763–770. DeVault KR, Castell DO. Guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Arch Intern Med 1995; 155:2165–2173. Hetzel D, Dent J, Reed W, et al. Healing and relapse of severe peptic esophagitis after treatment with Omeprazole. Gastroenterology 1988; 95:903–912. Ismail-Beigi F, Horton PF, Pope CE. Histological consequences of gastroesophageal reflux in man. Gastroenterology 1970; 58:163–174. Winter CS, et al. Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis. Gastroenterology 1982; 83:818. Spechler SJ. Complications of gastroesophageal reflux disease. In: Castell DO, ed. The Esophagus. Boston: Little Brown, 1995: 533–546. Katz PO, Dalton CB, Richter JE, et al. Esophageal testing in patients with noncardiac chest pain and/or dysphagia. Ann Intern Med 1987; 106:593–597. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease: a clinical investigation of 225 patients using ambulatory pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991; 101:1–78. Johnson LF, DeMeester TR. Twenty-four hour pH monitoring of the distal esophagus. Am J Gastroenterol 1974; 62:325–333. Dobhan R, Castell DO. Normal and abnormal proximal esophageal acid exposure: results of ambulatory dual probe pH monitoring. Am J Gastroenterol 1993; 88:25– 29. Schnatz PF, Castell JA, Castell DO. Pulmonary symptoms associated with gastroesophageal reflux: use of ambulatory pH monitoring to diagnose and to direct therapy. Am J Gastroenterol 1996; 91:1715–1718. Harding SM, Richter JE, et al. Asthma and gastroesophageal reflux: acid suppression therapy improves asthma outcome. Am J Med 1996; 100:395–405. Sontag S, O’Connell S, Khandelwal S, et al. Does wheezing occur in association with an episode of gastroesophageal reflux? Gastroenterology 1989; 96:482–490. Barrett J. Peghini P, Katz P, Castell J, Castell D. Ineffective esophageal motility (IEM): The most common abnormality in GERD (abstr). Gastroenterology 1997; 112:4. Palmer ED. The hiatus hernia-esophagitis-esophageal stricture complex. Twenty year prospective study. Am J Med 1968; 44:566–572. Sloan S, Kahrilas PJ. Impairment of esophageal emptying with hiatal hernia. Gastroenterology 1991; 100:596–605. Sloan S, Rademaker AW, Kahrilas PJ. Determinants of gastroesophageal junction incompetence: hiatal hernia, lower esophageal sphincter, or both? Ann Intern Med 1992; 117:977–982. Weiner GJ, Richter JE, Cooper JB, et al. The symptom index: a clinically important parameter of ambulatory 24 hour esophageal pH monitoring. Am J Gastroenterol 1988; 38:58–61. Kuo B, Castell DO. Optimal dosing of omeprazole 40 mg daily: effects on gastric and esophageal pH and serum gastrin in healthy controls. Am J Gastroenterol 1996; 91:1532–1538.

17. 18. 19. 20. 21. 22. 23.

24. 25.

26.

27. 28. 29.

30. 31. 32.

33.

34.

4 The Otolaryngologic Manifestations of GERD

JAMES A. KOUFMAN Wake Forest University School of Medicine Winston-Salem, North Carolina

I. Introduction It has been estimated that approximately half of otorhinolaryngology (ORL) patients with laryngeal and voice disorders have gastroesophageal reflux disease (GERD) as the primary cause or as a significant etiologic cofactor (1). This appears to be true for patients with diverse clinical manifestations (1,2); Table 1 lists the most common ORL symptoms and diseases that have been reported to be reflux-related. The mechanisms, patterns, and management of GERD in ORL patients appear to differ significantly from those of ‘‘typical’’ gastroenterology patients with esophagitis (1,5,20,25–29), and these differences are highlighted in this chapter. The reported association of gastric reflux with aerodigestive tract diseases is relatively recent. In 1935, the first detailed report linking gastric reflux with esophageal disease in adults was published by Winkelstein (30); in 1950, Berenberg and Neuhauser (31) reported reflux symptoms in children; and in 1968, Cherry and Margulies (15) first reported a reflux-related laryngeal disease (contact ulcer and granuloma). Many GERD-related laryngeal diseases have only been reported in the last two decades. Summarized in Table 2 are some of the important landmarks in the history of GERD. 69

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Table 1 Symptoms and Laryngeal Conditions Associated with GERD A. Symptoms: Chronic dysphonia Intermittent dysphonia Vocal fatigue Voice breaks Chronic throat clearing Excessive throat mucus Postnasal drip Chronic cough Dysphagia Globus B. Conditions associated with reflux as the cause or as a causative cofactor: Reflux laryngitis (2–6) Subglottic stenosis (2,3,7,8) Carcinoma of the larynx (2,6,9–13) Endotracheal intubation injury (2,14) Contact ulcers and granulomas (14–16) Posterior glottic stenosis (2,17) Unilateral or bilateral arytenoid fixation (2,14) Paroxysmal laryngospasm (18,19) Globus pharyngeus (2,20,21) Vocal nodules (1,2,5,22) Polypoid degeneration (1,2) Laryngomalacia (23,24) Pachydermia laryngis (2,9) Leukoplakia (2)

The etiologic role of gastroesophageal reflux (GER) in some airway diseases remains controversial and is still not accepted by all clinicians. Even among otolaryngologists who have a relatively high index of suspicion for GERD, it appears that reflux laryngitis, specifically called laryngopharyngeal reflux (LPR), is still often underdiagnosed and undertreated. There appears to be a four-part explanation for this phenomenon: 1. ORL patients with reflux laryngitis usually deny symptoms of heartburn and/or regurgitation. LPR may be ‘‘silent.’’ Fewer than half of ORL patients with LPR documented by pH monitoring complain of heartburn or regurgitation, symptoms that have traditionally needed to be present in order to diagnose GERD (1,2,5,14,20,29). 2. The findings of GERD on laryngeal examination vary considerably. Laryngeal edema, not erythema, is the hallmark of LPR, and may be overlooked as evidence of reflux laryngitis. Until recently, most otolaryngologists relied solely on the findings of posterior laryngitis (red arytenoids and piled-up, hypertrophic, posterior commissure mucosa) as the diagnostic sine qua non of reflux

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Table 2 Some Important Landmarks in the Study of Gastroesophageal Reflux Year

Person

Ref.

Landmark

1890 1899 1906 1921 1935 1940 1950 1964 1968 1972 1976 1980 1986

C. Jackson S. Meltzer W. Tileson H. Mosher A. Winkelstein F. Ingelfinger W. Berenberg F. Miller J. Cherry J. Delahunty H. Glanz R. Bogdasarian G. Weiner

32 33 34 35 30 36 31 37 15 4 9 17 28

1988

J. Koufman

Invents the esophagoscope Describes esophageal peristalsis Reports ‘‘gastric ulcer’’ of the esophagus Reports esophageal stricture Reports peptic esophagitis Introduces modern manometry Reports reflux symptoms in children Introduces prolonged pH monitoring Reports first reflux-related laryngeal disease Reports posterior laryngitis Reports reflux-related laryngeal cancer Reports reflux-related subglottic stenosis Introduces double-probe (pharyngeal and esophageal) pH monitoring Reports clinical findings and pH results of ORL patients with LPR

5

laryngitis. Unfortunately, these findings are not present in many LPR patients. Edema, not erythema, is the most prevalent finding of LPR. The edema may be diffuse, or it may create the illusion of sulcus vocalis, an appearance that is the result of subglottic edema (38). Figure 1(a) shows the typical appearance of the larynx of an LPR patient. 3. Traditional diagnostic tests for GERD lack both sensitivity and specificity for LPR. The diagnosis of LPR may be confounded by false-negative diagnostic tests. Barium esophagography, radionuclide scanning, the Bernstein acid-perfusion test, and esophagoscopy with biopsy are all usually negative in the ORL patient with LPR (2,20). They are negative because these tests primarily detect esophagitis, which is not commonly present in LPR patients (22,30). In addition, LPR is frequently intermittent, and exacerbations may depend to some extent upon changing dietary and lifestyle factors (2,5). 4. Therapeutic trials using ‘‘traditional’’ antireflux therapy often fail in ORL patients with LPR-related conditions, so that clinicians may falsely conclude that a diagnosis other than LPR may be the cause of the problem. The traditional treatment for GERD, particularly in the patient with esophagitis, includes dietary and lifestyle modifications and the use of antacids and H2 antagonists. Such treatment fails to control LPR in approximately 35% of ORL patients (2,39). In many cases, the intensity of the attempted treatment and the duration of the therapeutic trial are inadequate (2,25). Some clinicians mistakenly believe that a therapeutic trial of antireflux therapy for a few weeks duration is adequate, but that is not the case. Patients with long-standing reflux laryngitis often require months of optimal treatment with near-complete acid suppression to resolve their symptoms (2,16,25).

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Figure 1 Typical appearance of the larynx of a patient with LPR (A) before and (B) after treatment. (A) The most important findings of LPR are: (1) diffuse laryngeal edema; (2) obliteration of the laryngeal ventricles (the groove between the true and the false vocal cords); (3) pseudosulcus vocalis—due to subglottic edema—giving the true vocal cords the appearance of being thickened with a shallow trench down the middle; and (4) posterior commissure hypertrophy. (B) The same patient after 8 weeks of treatment with a proton pump inhibitor. Note that the vocal cords are thinner, the pseudosulci are gone, the ventricles are open, and the false cord edges are sharply defined. In addition, the patient has small, asymmetrical vocal nodules that were not seen before treatment.

II. Patterns and Mechanisms of Reflux in Otolaryngology Patients GERD is a common condition, but there appear to be two different populations of patients with GERD. When symptomatic patients with esophagitis seek medical attention, they usually see a gastrointestinal (GI) specialist; however, patients with hoarseness and other reflux-related throat symptoms usually see an ORL specialist. Until relatively recently, it was believed that a majority of patients with LPR presented with esophagitis and its principal symptom, heartburn. This is not the case. Esophagitis patients complain of dysphagia, eructation, regurgitation, and heartburn; symptoms that are frequently absent in patients with reflux laryngitis. Reflux laryngitis patients usually complain of multiple throat symptoms, including hoarseness, chronic throat clearing and cough, choking episodes, a globus sensation, or sore throat. Ossakow et al. (20) compared the reflux symptoms and findings in two discrete groups: ORL patients with reflux laryngitis (n ⫽ 63) and GI patients with esophagitis (n ⫽ 36). They reported that hoarseness was present in 100% of the ORL group and none of the GI group. Heartburn was present in 89% of the GI patients, but in only 6% of the ORL patients. Other authors have reported a low incidence of heartburn as a symptom of reflux laryngitis in ORL patients, ranging from 20 to 43% (1,2,14,29,39).

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Usually, ORL patients with reflux laryngitis do not present with the typical diagnostic findings of GI esophagitis patients. Wiener et al. (29) studied ORL patients with hoarseness and found that while 78% had abnormal pH studies, esophageal manometry was normal in 100%, esophagoscopy was normal in 72%, and the Bernstein acid-perfusion test was normal in 66%. Koufman (2) found that only 18% (23/128) of reflux laryngitis patients had findings of esophagitis on barium esophagography. Several reports of pH-monitoring data in ORL patients and GI patients have emphasized the typical difference in pattern (1,2,5,14,20,25,27–29). ORL patients typically have upright, daytime reflux, but not supine, nocturnal reflux. The pattern in GI patients is typically the opposite, i.e., most of the reflux is nocturnal (2,5,28,29). These same authors have also observed that the total esophageal acid-contact time of supine (GI) refluxers is typically longer than that of upright (ORL) refluxers. Esophageal acid clearance, the mean time that it takes for the esophageal pH to return to normal (neutral pH) after physiologic or pathologic reflux, is an excellent measure of overall esophageal function (40). Esophageal acid clearance can be calculated from the data of patients who have had ambulatory 24-hour pH monitoring. GI patients with documented erosive esophagitis have prolonged acid clearance due to esophageal dysmotility and sphincter dysfunction. Because ORL patients are predominantly upright refluxers, Koufman et al. (38) calculated the mean esophageal acid clearance in 88 patients with reflux laryngitis and compared the results to data from 10 GI patients with erosive esophagitis. The mean clearance for the ORL group was 0.94 ⫾ 0.23 minutes, while the mean clearance for the GI group was significantly longer ( p ⬍ 0.01) at 2.98 ⫾ 1.23 minutes. It has been postulated that otolaryngology patients with LPR often deny having heartburn and have a relatively low incidence of esophagitis because they are daytime, upright refluxers with relatively normal esophageal motility. These data support this hypothesis and reinforce the belief that most ORL patients with reflux laryngitis experience LPR by different mechanisms than those reported for GI patients with esophagitis. Experimental instillation of acid in the distal esophagus of normal subjects and patients with esophagitis usually results in a prompt increase in tone of the upper esophageal sphincter (UES) (41). This does not appear to be the case in ORL patients. Our studies have shown that the UES is not an effective barrier to prevent LPR in these patients (26). In summary, typical GI patients have supine, nocturnal reflux with prolonged esophageal acid clearance. This appears to be due to esophageal dysmotility and lower esophageal sphincter (LES) dysfunction. ORL patients typically have upright, daytime reflux with normal esophageal acid clearance. ORL patients have relatively good esophageal function, but faulty UES function. Thus, it appears that significant differences in the pattern of esophageal dysfunction

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Table 3 Differences Between Typical Patients with Reflux Laryngitis and Typical Patients with Esophagitisa

Symptoms Heartburn Hoarseness Globus, cough, etc. pH Monitoring Total abnormal Upright Supine Pharyngeal Other Diagnostic Tests Esophagoscopy & Bx Barium swallow Bernstein test Esophageal acid clearance UES manometryb H2-antagonist therapyc Failure rates

Laryngitis (%)

Esophagitis (%)

35 85 64

89 3 6

79 88 45 50

100 46 100 0 (Abnormal %)

27 38 30 7 50

100 68 89 70 0

35

10

a

This table represents a summary of data from many sources. Recognizing that some of the above numbers may not be completely accurate, this table is intended to provide the reader with an overview of the differences between ORL and GI patients with GERD. b J. A. Koufman, unpublished preliminary data (1997), N ⫽ 10. c High-dose ranitidine (600–1200 mg/day).

may explain some of the clinical differences between the two patient populations. Table 3 summarizes these differences. III. Acid and Pepsin Experimental reflux models in animals have shown that pepsin, and not acid, is responsible for producing tissue injury (2,8). Pepsin, however, requires activation by acid (42). Most animal models have evaluated perfusion of test substances on intact mucosal surfaces, e.g., esophagus, larynx. Using a canine model, Koufman (2) studied the effects of intermittent reflux on the subglottic region of the larynx after a mucosal injury had been created. Following mucosal abrasion, test substances were applied to the subglottic larynges of dogs on alternate weekdays for 2 weeks. The animals were then sacrificed, and the larynges were examined histologically in a blinded manner by a pathologist, who graded the inflammatory findings in a standard fashion. The animals’ larynges were painted with: (a) saline; (b) hydrochloric acid alone, pH 1.5, 2.5, and 4.0; or (c) acid and pepsin at the same pH values as the acid-only group. The data reveal that the animals

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painted with both acid and pepsin had significantly more severe tissue damage than the other two groups ( p ⬍ 0.001). These experiments show that when a mucosal injury precedes experimental reflux, even intermittent reflux can cause significant tissue injury to the larynx. Even though the animals experienced only three experimental reflux episodes per week for 2 weeks, half of the acid and pepsin animals had frank ulceration of the cricoid cartilage. In addition, these studies confirm that ‘‘acid’’ laryngitis is in reality ‘‘peptic’’ laryngitis, because activated pepsin is needed to produce significant tissue injury (2). These observations may also help explain why effective treatment of reflux laryngitis often requires acid-suppressive doses of a proton pump inhibitor (PPI).

IV. Clinical Manifestations The larynx, because of its position just above the UES, is a primary target for extraesophageal reflux. LPR may adversely impact other extraesophageal structures, such as the nose, sinuses, and ears (18,43). Since little is known about LPR events, such as the patterns of spread of the refluxate and its clearance, the effect of LPR on structures and organs above and below the larynx remains to be elucidated. Even among otolaryngologists, there is no uniform consensus as to the role of LPR in many diseases of the head and neck. Unfortunately, there are still very few reflux-testing data on the relationship between LPR and conditions such as sinusitis and otitis media. Most of the available clinical data in ORL is related to the relationship between LPR and laryngeal diseases (Table 1). In a large series of ORL patients with reflux laryngitis and documented LPR, 92% presented with dysphonia (hoarseness) (2). Additional symptoms were experienced by the majority of the patients: chronic throat clearing (50%), chronic cough (44%), globus (sensation of ‘‘lump in throat’’) (33%), and dysphagia (27%). The pattern of dysphonia was either chronic or intermittent. Patients with intermittent dysphonia often complain that they suffer from laryngitis that lasts for days or weeks, several times a year. Half of the patients denied having any heartburn whatsoever; 13% had two or fewer episodes per week, 27% had two to four episodes per week, and only 10% complained of more frequent or daily heartburn (2). The clinical manifestations of LPR in ORL patients can be divided into three groups, based upon severity: life-threatening, major, and minor. Although most patients with reflux laryngitis present with mild to moderate dysphonia as the primary symptom, some suffer from more serious, even life-threatening, conditions. Less common laryngeal manifestations of LPR include laryngospasm, arytenoid fixation, laryngeal stenosis, and carcinoma. LPR is also associated with the development of polypoid degeneration (Reinke’s edema), vocal nodules, and other functional voice disorders.

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Table 4 Relative Severity of Symptoms and Sequelae Related to Laryngopharyngeal Reflux Minor Dysphoniab (in the ‘‘nonvocal professions’’) Ulcer/Granulomab (in the ‘‘nonvocal professions’’) Globus Dysphagia Chronic throat clearing Chronic cough

Major

Life-threateninga

Dysphoniab (in a vocalist or professional speaker) Ulcer/granulomab (in a vocalist or professional speaker) Leukoplakia Pachydermia Dysplasia Chronic coughc

Subglottic stenosis Posterior laryngeal stenosis Arytenoid fixation Carcinoma (especially in nonsmokers) Laryngospasm

a

The ‘‘life-threatening’’ group is defined by either airway obstruction or malignancy The purpose of establishing a ‘‘difference’’ between the ‘‘severity’’ (of the same symptom) in the vocalist and the nonvocalist is to emphasize that economic and emotional consequences of a voice disorder depend on the vocal needs and demands of each patient. When a professional vocalist, for example, develops a voice disorder, this may have profound consequences, and thus effective treatment must be maximized (see text). c On occasion, this symptom may be so severe that the patient is relatively incapacitated. Note: A professional speaker is a person for whom a good voice is essential to his or her profession, e.g., lecturer, minister, telephone operator. b

The severity of the clinical manifestations (Table 4) influences the clinician’s approach to the diagnosis and treatment of each of the three patient groups. Each group is managed differently. Patients with airway obstruction and malignant neoplasia are considered to have life-threatening reflux. Those with other, less severe symptoms and findings are subgrouped into the major or minor groups. Those subgroup determinations are not only based upon the severity of the clinical situation, but also take into account the vocal needs and occupation of the patient. A.

Functional Voice Disorders

The term functional voice disorder (FVD) applies to a variety of vocal abuse/ misuse/overuse syndromes. The FVD conditions are often associated with the development of secondary histopathologic changes in the vocal cords, which include hematomas, nodules, ulcers, granulomas, and Reinke’s edema. Available pH-monitoring data suggest that the majority of patients with these functional lesions have LPR in addition to abnormal (or altered) laryngeal biomechanics (22). In many cases, LPR may have precipitated the problem (1). As part of the evaluation of each patient with a FVD, the clinician should elicit a reflux history. Patients who have posterior laryngeal erythema, edema, or thick mucus in the endolarynx should be suspected of having LPR. Although

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treatment of LPR alone does not resolve all FVDs, such is the case in some patients. Failure to treat reflux laryngitis, when it is present, may doom what otherwise would be an effective therapeutic intervention. The laryngeal findings of a patient with a FVD may be subtle, ranging from increased endolaryngeal mucus and subglottic edema to ulceration and granulation. Subglottic edema may give the appearance of a subglottic groove or vocal fold sulcus, i.e., a pseudosulcus. This finding should alert the clinician to the possibility of LPR. Mucus in the larynx is not usually the result of infection or postnasal drip. This finding is generally the result of a local tissue (inflammatory) response to chronic irritation. Ulceration and granulation can be seen in non-LPR patients; however, most patients who present with these findings have both reflux and abnormal vocal usage. B. Granulomas

Some patients with reflux laryngitis develop granulomas of the arytenoids. The etiology of these lesions is multifactorial; however, LPR should always be suspected. Granulomas often result from the combination of acute mucosal ulceration of the vocal processes, LPR, and chronic vocal trauma due to throat clearing and/or vocal abuse (16). The clinician should, in each case, consider each of the possible contributing etiologic factors and correct each one if therapy is to be effective. Effective antireflux therapy (twice-daily PPI) is sufficient to allow healing in the majority of patients. Surgical removal of granulomas is uncommonly indicated, except when (a) lesions appear suspicious for malignancy (they should be excised for biopsy), (b) large granulomas cause airway obstruction, and (c) granulomas mature and become fibroepithelial polyps (16). C. Paroxysmal Laryngospasm

Laryngospasm is an uncommon complaint, but patients who experience this frightening symptom are usually able to describe events in vivid detail. If the clinician mimics severe inspiratory stridor, the patient will confirm that his or her breathing during an attack does indeed sound similar. Laryngospasm is sometimes confused with asthma; however, if the patient is asked whether the problem is ‘‘getting air in’’ or ‘‘getting it out,’’ the patient with true laryngospasm will always say ‘‘in.’’ Laryngospasm is often paroxysmal, and it usually occurs without warning. For some patients, the attacks awake them from sleep. In some cases, the attacks may have a predictable pattern, e.g., postcibal or during exercise. Some patients are aware of a relationship between LPR and the attacks, others are not. Loughlin and Koufman (19) reported that of 12 patients who presented with recurrent paroxysmal laryngospasm, 11 had documented LPR by pH testing and all 12 responded to treatment with a PPI (omeprazole) with a complete cessation of the laryngospasm episodes. Using a canine model, Loughlin et al. (44) demonstrated that acid stimula-

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tion (pH ⬍ 2.5) of chemoreceptors, ‘‘taste buds,’’ on the epiglottis caused reproducible laryngospasm. The laryngospasm reflex was documented to occur independent of pepsin concentration and tonicity of test substances. This reflex is mediated by the superior laryngeal nerves. This and other studies suggest that reflux-related laryngospasm may be a cause of sudden infant death syndrome (SIDS) (45–48). D.

Polypoid Degeneration (Reinke’s Edema)

Polypoid degeneration results from chronic laryngeal irritation over a period of many years. It is almost always bilateral and occurs most frequently in elderly female smokers. Nevertheless, it is also seen is nonsmoking patients with LPR or hypothyroidism. Most patients with polypoid degeneration have abnormal pH testing (1). Consequently, LPR should be considered in the differential diagnosis. Polypoid degeneration may improve with antireflux therapy and cessation of smoking, but most patients with these lesions require surgical treatment as well. Patients undergoing vocal fold surgery for this condition should receive antireflux treatment during the perioperative period. E.

Laryngeal Stenosis

The primary cause of laryngeal stenosis, including subglottic and posterior laryngeal stenosis, is LPR (2,3,8,17). Reflux documented by pH testing has been found in 92% of cases (2). Treatment with PPIs or fundoplication will result in subsequent decannulation of the vast majority of patients with stenosis, in some cases without additional laryngeal surgery. pH monitoring and antireflux therapy are routinely indicated in all cases of laryngeal stenosis, and high-dose PPI treatment and fundoplication are essential adjuncts to laryngeal rehabilitative surgery. F. Carcinoma of the Larynx

LPR is an important risk factor for the development of laryngeal carcinoma (1,2,6,9–13). Koufman and Cummings (6) reported a prospectively evaluated series of 50 patients with early laryngeal carcinoma in which abnormal reflux was documented in 72%, while only 44% were active smokers. The remaining subjects were 42% ex-smokers (with a median duration of smoking cessation of 8 years) and 14% lifetime nonsmokers. The relationship between LPR and malignant degeneration of the laryngeal mucosa remains to be proven, but the available reflux testing data suggest that most patients who develop laryngeal malignancy both smoke and have LPR (2,6,12,13). For nonsmokers who develop laryngeal cancer, LPR appears to the single most important risk factor (6,11). Laryngeal carcinogenesis appears to be multifactorial (11). Previously identified risk factors, i.e., tobacco and ethanol, also strongly predispose one to reflux (2,6,49–51). Tobacco and alcohol adversely influence almost all of the body’s

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antireflux mechanisms; they delay gastric emptying, decrease lower esophageal sphincter pressure and esophageal motility, decrease mucosal resistance, and increase gastric acid secretion (49–51). In a carefully controlled case study, Guenal et al. (52) showed that the major risk factor for the development of supraglottic carcinoma is ethanol consumption and not tobacco. Koufman has reported six patients with apparently premalignant vocal cord lesions (leukoplakia) that resolved, i.e., disappeared, with antireflux therapy alone (2). Routine reflux testing, followed by PPI treatment, is recommended for all patients with laryngeal neoplasia even when other risk factors for the development of carcinoma of the larynx are present. G. Dysphagia, Globus Pharyngeus, and Other Reflux-Related Cervical Symptoms

Dysphagia (difficulty swallowing), globus pharyngeus (a sensation of a lump in the throat), and chronic sore throat are all symptoms that may be caused by LPR. Reflux commonly causes these symptoms (2,20,21). With this group of symptoms, however, it is incumbent on the clinician to rule out other inflammatory disorders and mass lesions, e.g., hypopharyngeal carcinoma, cervical osteophyte, foreign body, thyroid goiter. With the above symptoms, contrast barium study is recommended as the first diagnostic test after the examination is completed. In addition, if the patient has reflux findings, then manometry and pH monitoring are obtained. Several mechanisms for dysphagia and globus are reflux-related: (a) patients may have distal esophagitis, without true LPR, and experience these cervical symptoms; (b) patients with LPR may have UES dysfunction, characterized by high resting UES pressure and discoordinated (usually delayed) UES opening; and (c) patients may have sufficient LPR with gastric contents bathing laryngopharyngeal structures, so that throat symptoms are caused by local inflammation and swelling. Ossakow et al. (20) reported that ORL patients with cervical symptoms usually have actual LPR. The pattern of reflux in this group is similar to that of ORL patients with other LPR symptoms and different from GI patients with esophagitis. The findings of Koufman were somewhat different; he found that ORL patients with globus and dysphagia frequently have esophageal dysfunction, including dysmotility, esophagitis, and stricture formation, more frequently, compared to other ORL patients with LPR (2). H. Xerostomia and GERD

Xerostomia, dryness of the mouth, commonly encountered in otolaryngologic practice is a major risk factor for the development of GERD. Salivary bicarbonate is needed to restore the intraluminal esophageal pH after a reflux episode. Without

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normal saliva, the esophageal pH remains very low for an extended period of time (40). Xerostomia is commonly seen with sicca syndrome, Sjo¨gren’s syndrome, scleroderma and most other collagen vascular diseases, cystic fibrosis, and with many medications (e.g., anticholinergics, antihypertensives, antihistamines). Head and neck irradiation also produces xerostomia. Rosman et al. (53) studied seven ORL patients with head and neck irradiation. All had normal esophageal motility; however, six of the seven had abnormal esophageal acid clearance and abnormal pH-monitoring results. I.

Laryngopharyngeal Reflux in Pediatric Patients

Pediatric patients also suffer from LPR; dysphonia, laryngospasm, laryngomalacia, and pulmonary disorders, such as asthma, have been shown to be related to LPR in infants and children (18,23,24,31). A recent report documented LPR in 93% of ORL pediatric patients with airway diseases (23) Double-probe pH monitoring is especially useful in diagnosis of pediatric patients. They seldom complain of symptoms. The double probe is recommended because of its enhanced sensitivity for LPR, the sensitivity of single-probe pH testing being only 47% (23). The treatment algorithms presented herein apply to infants and children; however, it is more difficult to administer and dose PPIs in pediatric patients. Therefore, H2 antagonists and fundoplication are commonly employed in pediatric patients with LPR.

V.

Diagnosis

When a patient presents with symptoms of reflux laryngitis, the clinician should perform a complete otolaryngologic examination. This includes fiberoptic laryngoscopy and photography of the larynx. Ambulatory 24-hour double-probe pH monitoring and barium esophagography should be considered. Double-probe (simultaneous esophageal and pharyngeal) pH monitoring has a tremendous advantage over any other diagnostic method because it is both highly sensitive and specific (29,54). Furthermore, pH monitoring reveals the pattern of reflux, so that subsequent treatment can be custom-tailored for each patient. For example, if the patient does not have supine nocturnal reflux, elevation of the head of the bed is not necessary. pH monitoring has been available for many years, and standards (normal values) have been established in many laboratories (2,54). The single most important parameter is generally regarded to be the percentage of time that the pH is less than 4. This measurement is usually calculated for time in the upright position, time in the supine position, and the total time of the study. For the upright position, the upper limit of normal is approximately 8.0%, and for the supine position, approximately 2.5% (2,54).

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A. The Pharyngeal Probe in ORL Patients with LPR

Detection of pharyngeal reflux episodes during double-probe pH monitoring, with the second probe being placed behind the larynx just above the cricopharyngeus, is indicative of laryngopharyngeal reflux. In our laboratory, none of 20 normal controls had any documented pharyngeal reflux episode (29). Therefore, it may be concluded that even a single pharyngeal reflux episode should be considered diagnostic of LPR (2,26). Double-probe pH monitoring is particularly important in ORL patients because otherwise the diagnosis might be missed. Recently, it was shown that 37% (28/75) of a consecutive series of ORL patients with abnormal pH testing had normal total acid exposure times in the esophagus, but still had pharyngeal reflux (26). In other words, were it not for the pharyngeal probe findings, these 28 patients would have been falsely presumed not to have reflux. Pharyngeal probe pH monitoring is necessary in ORL patients because it significantly increases the diagnostic yield (sensitivity) of pH monitoring from 50 to 75% (26). B. Barium Esophagography or Esophagoscopy

It is also advisable to perform a barium swallow/esophagogram or esophagoscopy in ORL patients with LPR to assess the integrity of the esophageal lining (2,55). Although contrast studies are not a sensitive way to diagnose LPR, they may demonstrate significant esophageal abnormalities that might otherwise be missed. In a series of 128 patients, the results of barium study revealed that 18% had esophagitis, 14% had a lower esophageal ring, and 3% had a peptic stricture (2). Since so few ORL patients with LPR have esophagitis, esophagoscopy is not routinely recommended except for elderly Caucasian men, who are at increased risk of developing Barrett’s esophagus and esophageal cancer. VI. Treatment The larynx is far more susceptible to peptic injury than the esophagus, because it does not have acid-clearance mechanisms (peristalsis and salivary bicarbonate) and because its mucosa is thin, fragile, and poorly adapted to protect against reflux. For some patients with LPR, treatment with lifestyle modifications and an H2 antagonist is appropriate initial therapy; however, treatment failure can be expected in approximately 35% (2). The problem with H2 antagonists is that they do not adequately suppress gastric acid. Pepsin, the actual injurious agent in the refluxate, is acid-activated, and at pH 4.5 70% of peptic activity remains (2,56). Since the patient’s gastric pH is less than 4 at the therapeutic nadir, activated pepsin is present several times each day and can produce significant injury. In other words, for patients with LPR in whom even infrequent LPR may cause laryngeal damage, H2 antagonists may be inadequate treatment.

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The PPIs (omeprazole and lansoprazole) have revolutionized antireflux treatment for reflux-related esophageal disease (57–61) and for LPR (19,25,39,62,63). However, even when treated with relatively large daily doses of PPI, many patients with LPR will not experience resolution of their symptoms until after several months of treatment. In 1996, a consensus conference of otolaryngologists on LPR suggested that the duration of therapy with PPI should be 6 months (25). In addition, PPI therapy is also useful in difficult-to-diagnose cases. Until the availability of PPIs, a trial of antireflux medication had little validity as a diagnostic test. On the other hand, a therapeutic trial of PPI therapy may be used as a diagnostic test, but again, it is important not to underdose or to treat for too short a period of time. Treatment of LPR requires considerable individualization with the level of treatment depending on the severity of the patient’s condition. Obviously, clinicians have fewer treatment options for patients with life-threatening or major LPR than in patients with minor reflux. In creating treatment algorithms, consideration must be given to both the initial treatment period and long-range therapy (years). Hence, the age and the occupation of the patient must also be considered in formulating treatment plans. A.

Treatment of Life-Threatening LPR

Ideally, all patients with laryngeal carcinoma, stenoses, and laryngospasm should undergo pH monitoring and manometry before antireflux treatment is started. This is not always possible, particularly if the patient requires emergency surgical treatment such as tracheotomy. Nevertheless, every effort should be made to obtain these studies prior to treatment, because (a) it establishes the diagnosis, (b) it determines the severity of the GERD, (c) it establishes baseline manometric parameters, (d) it allows treatment to be individualized, and (e) in selected cases, it justifies unconventional treatment. Initial treatment in these patients should be with high-dose PPI, e.g., omeprazole 40–60 mg or lansoprazole 60–90 mg, as well as with dietary and lifestyle modification. In the event that the patient is unable to take an orally administered medicine, an intravenous ranitidine drip should be employed, and the gastric contents should be neutralized using antacids and/or continuous enteral alimentation. In selected cases (particularly young patients) with the most severe form of LPR, fundoplication should be considered as an early alternative. If, for example, a young person presents with laryngeal airway obstruction, no prior history of trauma or intubation, and pH evidence of severe reflux with a very low LES pressure on manometry, then fundoplication is probably the first and best antireflux treatment. While this situation is uncommon, it does occur. For most patients, PPIs are the treatment of choice for at least the first 6 months, or until such time as the clinical situation that prompted the intervention has resolved. It is injudicious to stop or taper PPIs in patients with laryngeal

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stenosis still undergoing treatment for the stenosis. Since some of these patients present with airway obstruction severe enough to require tracheotomy, PPI treatment should be continued until the patient has been successfully decannulated, and it is clear (by repeat pH testing) that reflux is under control. In practice, most patients with stenosis will require either chronic PPI therapy or fundoplication. The same is true for many patients with carcinoma of the larynx, especially non smokers who develop carcinoma. In this group, the risk of the patient developing new lesions exceeds the risks of definitive long-term antireflux treatment. In 1989, when omeprazole was introduced in the United States, The Food and Drug Administration recommended that it be used in a dose of 20 mg per day for only 6–8 weeks. It was soon clear that this regimen was woefully inadequate to treat many ORL reflux patients (25,39). Fortunately, long-term omeprazole therapy has been used extensively, and it is now believed to be safe and effective as a long-term therapy (64–66). In patients with life-threatening LPR over the age of 60 years, chronic, long-term PPI treatment is recommended. On the other hand, if the patient has only supine or upright reflux disease, but not both, a single daily dose may suffice for maintenance after the acute phase of the illness has resolved. For patients under 40 years of age, fundoplication is usually recommended, and for patients between the ages of 40 and 60 years, treatment is selected on an individual basis. In the latter situation, the severity of the LPR and of the underlying ORL condition is considered, as well as the preferences of the patient and his or her overall medical condition. B. Treatment of Major LPR

The initial phase of treatment for patients in this group is similar to that outlined above, except that fundoplication is rarely considered. As a rule, the first 6 months of treatment should consist of PPI therapy and a program that optimally manages the patient’s diet, weight, and lifestyle: (a) smoking cessation (if the patient smokes) (b) weight reduction (if the patient is overweight), (c) avoidance of overeating and night-eating, (d) a low-fat diet, and (e) avoidance of known ‘‘refluxogenic’’ foods, such as coffee, chocolate, mints, and carbonated beverages. The initial phase of antireflux therapy has two simultaneous goals: to arrest the inflammatory process in the larynx and, if possible, to reconstitute the body’s normal antireflux defenses (2,67). After 6 months of PPI therapy, if the patient’s larynx has returned to normal, and assuming good patient compliance, the PPI dose may be tapered. The patient may then want to try using an H2 antagonist. The patient should be followed closely during the therapeutic adjustment period. If the patient appears to be failing medical treatment at any time, repeat pH monitoring should be obtained while the patient is continuing to take the medication to evaluate the efficacy of treatment. In this way, medical treatment failure can be objectively documented. When this situation is encountered, the clinician must consider other therapeutic options.

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Treatment of Minor LPR

In most ORL practices, the minor reflux group comprises a majority of patients with reflux laryngitis. Minor reflux patients typically have symptoms of intermittent dysphonia, chronic throat clearing, globus pharyngeus, and dysphagia and findings such as laryngeal edema and posterior laryngitis. It is appropriate for the clinician to adopt a less aggressive and more conventional approach to the management of patients in this group. Clearly, it is not essential to obtain pH monitoring in all of these patients prior to treatment. Furthermore, conventional antireflux therapy is sufficient for many patients in this group. If initial therapy fails, the medication type and dosage should be escalated in a stepwise fashion. Patients who fall into the minor reflux group, based upon the symptoms and findings, should be managed conservatively if they do not have laryngeal lesions for which surgery is contemplated. It is prudent to treat all patients undergoing laryngeal surgery with PPIs. The PPI should be started prior to, and continued after, surgery, until healing of the larynx is complete. The routine use of perioperative omeprazole appears to decrease postoperative complications of laryngeal surgery and enhance the results (1,6). VII.

Reflux, the Internal Environment, and a New Paradigm of Airway Disease

We are at a crossroads in terms of our understanding of LPR/GERD. It is the likely cause of, or a primary catalyst for, many inflammatory and neoplastic diseases of the airway, including some occurring apart from the laryngopharynx. Reflux may also influence regulatory functions and vagal reflexes, both normal and maladaptive (e.g., the possible relationship between LPR and SIDS). Based upon clinical and double-probe pH-monitoring data, the sensitivity of pH testing using the current state-of-the-art instrumentation for the diagnosis of LPR is at best 80% (1,2,5,6). The problem, however, is not the instrumentation, but rather that LPR is frequently intermittent. In addition, demonstration of a LPR event by pH testing does not prove causality, i.e., that LPR is the cause of disease. Until recently, the medical community may have underestimated the impact of LPR/GERD on airway diseases, because LPR is often silent, intermittent, and therefore, sometimes difficult to diagnose. Research is needed in three areas. The first is epidemiology. Little is known about the prevalence and incidence of premorbid and symptomatic LPR. In a study of a community-based cohort of 100 adults, Reulbach et al. (68) found that 70% of people over the age of 40 years had symptoms and findings of reflux laryngitis. Subclinical LPR may be ubiquitous, and its impact on airway diseases may be profound. The second area is vagal physiology, including (a) normal and abnormal vagal reflexes, (b) relationships and interactions between the regulatory functions

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of different organs supplied by the vagus, and (c) the impact of exogenous diseases, e.g., viral infection or trauma, on vagal function and LPR/GERD. The third area is related to the impact of reflux on a cellular level, including (a) humoral responses of airway mucosa, (b) cell membrane permeability and damage, and (c) metaplasia, neoplasia, and carcinogenesis. It seems reasonable to propose that a multitude of interrelated factors (genetic, anatomic, neuromuscular, and inflammatory) may influence LPR/GERD and that LPR/GERD, even when ubiquitous and silent, may adversely influence the internal environment in significant ways. Development of such a new paradigm of LPR/GERD will require a multidisciplinary approach. VIII. Conclusion Laryngopharyngeal reflux is an illusive, ubiquitous, and pernicious cause of laryngopharyngeal inflammatory and neoplastic disorders. Frequently underdiagnosed and undertreated, LPR is believed to be an etiologic factor in approximately half of patients with laryngeal and voice disorders. The pervasive and serious nature of LPR in laryngology demands that clinicians caring for patients with laryngeal and voice disorders consider this diagnosis in almost every case. The most important advances in the management of LPR are ambulatory 24-hour double-probe pH monitoring and the proton pump inhibitors. These have revolutionized the diagnosis and treatment of reflux in otolaryngology. References 1.

2. 3. 4. 5. 6.

7.

Koufman JA, Cummins MM. The prevalence and spectrum of reflux in laryngology: a prospective study of 132 consecutive patients with laryngeal and voice disorders. Presented at the Meeting of the Southern Section of the American Laryngological, Rhinological and Otological Society, Inc., Naples, FL, January 10, 1996. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease. Laryngoscope 1991; 101(Suppl 53):1–78. Bain WM, Harrington JW, Thomas LE, et al. Head and neck manifestations of gastroesophageal reflux. Laryngoscope 1983; 93:175–179. Delahunty JE. Acid laryngitis. J Laryngol Otol 1972; 86:335–342. Koufman JA, Wiener CJ, Wu W, et al. Reflux laryngitis and its sequelae: the diagnostic role of ambulatory 24-hour pH monitoring. J Voice 1988; 2:78–89. Koufman JA, Cummins MM. Reflux and early laryngeal carcinoma: a prospective study using pH monitoring. Presented at the Meeting of the Southern Section of the American Laryngological, Rhinological and Otological Society, Inc., Key West, FL, January 7, 1995. Jindal JR, Milbrath MM, Shaker R, et al. Gastroesophageal reflux disease as a likely cause of ‘‘idiopathic’’ subglottic stenosis. Ann Otol Rhinol Laryngol 1994; 103: 186–191.

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5 GERD A Major Factor in Chronic Cough

CURTIS J. MELLO Brown University School of Medicine Providence, Rhode Island

I. Introduction Cough is a common symptom for which patients seek medical attention. Approximately 30 million visits to primary care physicians occur each year because of cough (1). Cough is the third leading cause for seeing an office-based internist (2,3). The economic impact of cough is significant. Over $500 million are spent each year on cough and cold preparations (1). Cough can be caused by a multiplicity of factors. Although it is beyond the scope of this chapter to discuss every cause of cough, and it is important for the reader to become familiar with some of the most frequent causes of cough and to consider gastroesophageal reflux as a cause of cough. There are three important distinguishing considerations when evaluating the cause of cough: duration, smoking status, and findings on chest roentgenogram. Cough can be acute or chronic. Chronic cough is defined most frequently as a cough lasting longer than 3 or 4 weeks (3–8). The most frequent cause of an acute cough is the common cold (3). The presence or absence of cigarette smoking is the single most important consideration in assessing the cause of persistent cough. Smokeinduced airway inflammation is the most common cause of chronic cough in cigarette smokers (1,10,11). The consideration of causes of chronic cough differs 89

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depending on the presence or absence of a normal chest roentgenogram. Puolijoki and Lahdensuo (12) studied 198 patients with cough lasting longer than 2 months. Among the 51 patients with abnormal chest roentgenograms, lung cancer and sarcoidosis were the two most frequent causes of cough. Asthma and postnasal drip were most commonly implicated as the etiologies of cough in the 147 patients with a normal chest roentgenogram. Asthma and postnasal drip have been found to be among the most frequent causes of cough in nonsmokers with a normal chest roentgenogram in a number of other studies as well (4,5,7,8,13– 17). Gastroesophageal reflux has been implicated as a cause of chronic cough in numerous studies (4,5,7,9,14,17–32). Depending on the clinical setting, i.e., primary care setting or referral center, GER-induced cough accounts for 4–24% of the cases of chronic cough (4,5,14,17,18). In nonsmokers with normal chest roentgenograms who are not using angiotensin-converting enzyme inhibitors and in whom asthma and postnasal drip have been ruled out, gastroesophageal reflux is the most frequent cause of chronic cough (5,7,12,13,16). Irwin et al. (5) demonstrated that GER was the third most frequent cause of cough in 102 consecutive and unselected patients evaluated for chronic cough, with only postnasal drip and asthma being more prevalent, respectively (Fig. 1). Furthermore, gastroesophageal reflux was found to be the cause of cough in 21% of patients. Hoffstein (6) obtained similar results when he evaluated 228 patients with persistent cough. Gastroesophageal reflux was found to be involved in causing cough in 24% of patients and again was only less common than postnasal drip and asthma as the etiology of persistent cough in nonsmokers with normal chest roentgenograms. Smyrnios (9) also found that gastroesophageal reflux was the most common cause of cough in patients who fit the aforementioned clinical profile. Fitzgerald et al. (24) was able to control cough in 14 of 20 patients with a 3-month course of medical antireflux therapy in whom no cause of cough could be found. In 5 of the remaining 6 patients, a more invasive evaluation confirmed gastroesophageal reflux. Four of these five patients underwent fundoplication and were asymptomatic 3 months after surgery. The relationship between gastroesophageal reflux and persistent cough is not limited to any particular age group. Smyrnios et al. (16) demonstrated that gastroesophageal reflux is a common cause of cough in the elderly, while Holinger and Sanders (13) obtained similar results in 72 infants and children under the age of 16 years. There are some who are skeptical of gastroesophageal reflux playing a causative role in cough. Laukka et al. (33) studied 10 patients with chronic cough using pH probe monitoring. Eighty-two percent of cough episodes had no correlation with gastroesophageal reflux. Of those episodes where cough and gastroesophageal reflux were felt to be related, only 30% of coughs followed episodes of gastroesophageal reflux. The authors concluded that gastroesophageal reflux

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Figure 1 The causes of chronic cough. Top panel. The cause was determined in 99% of patients; it was due to a single condition in 73% of patients and to multiple disorders in 26%. Bottom panel. The spectrum and frequency of the 131 causes (PND ⫽ postnasal drip syndrome; GER ⫽ gastroesophageal reflux; Bronch ⫽ bronchitis; bronchiect ⫽ bronchiectasis; misc ⫽ miscellaneous). Reprinted with permission from Ref. 5.

is not a frequent cause of chronic cough. In another study, instillation of 0.1 N HCl into the esophagi of anesthetized cats failed to induce cough (34). It should be emphasized, however, that despite these two studies there is a preponderance of evidence linking gastroesophageal reflux to cough. Cough can be caused by a multitude of factors in any one patient. The suspicion that cough may be caused, at least in part, by GER should be raised

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if cough has only partially improved with treatment directed at the other more common causes of cough, i.e., postnasal drip and asthma. Irwin et al. (5) demonstrated that cough may have multiple causes in a study of 102 patients with chronic cough, while Mello et al. (7) found that the cause of cough was multifactorial in 59% of 88 patients with persistent cough. Smyrnios et al. (9) concluded that cough was caused by two or more etiologies in 62% of patients with chronic cough with excessive sputum production. In all three studies, gastroesophageal reflux was determined to be a major cause of cough, frequently in combination with other disorders. Euler et al. (28) studied 30 children with recurrent pulmonary disease and gastroesophageal reflux disease proven by esophagram, esophageal manometry, pH probe testing, or esophagoscopy with biopsy. Nineteen of the 30 children studied had a history of nocturnal cough, and all had a history of asthma or previous pneumonia. Sixty-three percent of subjects were found to have underlying gastroesophageal reflux.

II. Pathophysiology In order to understand how gastroesophageal reflux may cause cough, one needs to have a basic understanding of the cough reflex. The involuntary cough reflex is a vagally mediated function. Cough can only be initiated from structures innervated by the vagus (35). Afferent cough receptors are located in the laryngeal and tracheal mucosa, the mucosa of large bronchi, the tympanic membrane and external auditory canal, and possibly throughout the mucosa of the esophagus. Receptors in the laryngeal and tracheobronchial tree belong to a class of receptors called rapidly adapting irritant receptors (3,36–40). These receptors are activated by a number of mechanical and chemical stimuli including mucus, dust, foreign bodies, tobacco smoke, acid and alkaline solutions, as well as inflammatory mediators (3). Impulses from afferent receptors travel via various neural pathways to the medulla oblongata within the brainstem, where synapses with motor outputs occur (13). Motor outputs to the respiratory muscles originate in the nucleus retroambigualis, whereas motor neurons to the larynx and tracheobronchial tree begin in the nucleus ambiguus. It is important to note that these same afferents may also stimulate submucosal glands within the airways to secrete mucus (3,38,39). It is not clear, however, whether these same afferents also cause bronchial smooth muscle contraction or if another class of afferents is responsible for bronchoconstriction following exposure to various stimuli that are known to cause both cough and bronchospasm (40). In addition to the tracheobronchial cough reflex, several investigators also have postulated a vagally mediated tracheobronchial-esophageal reflex (19,20,41–44). It is believed that there are afferent receptors within the esophageal mucosa that, when stimulated by exposure

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to acid and possibly alkali, send impulses to the previously described cough center within the brainstem, triggering outputs along motor neurons to the respiratory muscles and tracheobronchial tree and resulting in cough. Finally, the esophagoglottal and phyaryngoglottal reflexes promote closure of the vocal cords and introitus to the trachea, protecting against retrograde aspiration of gastroesophageal contents (45). As one can envision, gastroesophageal reflux can cause cough via two basic mechanisms: aspiration and/or neural reflex arcs. Gross or microaspiration of gastric/esophageal contents is a well-known cause of cough. Chernow et al. (23) studied six patients with chronic respiratory symptoms suspected of having nocturnal aspiration from gastroesophageal reflux using pH monitoring and gastric instillation of technetium 99m sulfur colloid. Lung scans were performed 8 hours after placement of technetium in the stomachs of subjects. Three of the six subjects were found to have radioactive uptake within the lungs by lung scanning, and all three had prolonged episodes of gastroesophageal reflux on pH monitoring. Fujimori et al. (46) reported a patient with nocturnal cough and frequent heartburn. Upper gastrointestinal roentgenogram demonstrated reflux of barium into the proximal esophagus, while esophageal endoscopy revealed reflux esophagitis. Bronchial biopsy specimens showed chronic inflammatory changes. The patient’s cough improved after a course of therapy directed at gastroesophageal reflux. Nussbaum et al. (47) demonstrated the presence of lipid-laden macrophages in 85% of 74 children with chronic respiratory tract symptoms and proven gastroesophageal reflux. Grading the number of lipid-laden alveolar macrophages seen on tracheal aspirates has also been shown to correlate with the presence of gastroesophageal reflux in children (48). Gastroesophageal reflux with resultant microaspiration of gastric contents has been implicated in the development of pulmonary dysfunction in patients with progressive systemic sclerosis (49). Tracheotomized patients are at risk for aspiration (50) even in the presence of a gastrostomy tube (51). Therefore, gastroesophageal reflux with occult aspiration should be considered in these individuals, especially if they are experiencing chronic cough and/or recurrent pneumonias. In a study of gastroesophageal reflux in asthmatics and chronic bronchitics, Ducolone et al. (52) demonstrated that pulmonary aspiration was present in 21% of patients with reflux. The second mechanism by which gastroesophageal reflux causes cough is through neural reflex arcs. As previously stated, several investigators have suggested a reflex arc between the esophagus and trachebronchial tree (see Chap. 2) (19,20,41–44,53). It is believed that the esophageal mucosa contains afferent receptors, which, when stimulated by mechanical and chemical stimuli, send impulses to the cough center, which, in turn, generates motor outputs along efferents to the respiratory muscles involved in the generation of cough. It is critical to understand that under this mechanism, aspiration of gastroesophageal contents

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is not required for the precipitation of cough. Irwin and colleagues (42) studied nine patients with chronic cough using prolonged esophageal pH monitoring. Both the proximal and distal portions of the esophagus were monitored. Coughs simultaneously occurred with a pH ⬍ 4 in the distal esophagus 35% of the time and only 8% of the time in the proximal esophagus. Furthermore, coughs only correlated with distal esophageal events, suggesting that microaspiration was not necessary for developing cough. In another study (20), 12 individuals with chronic cough were evaluated. All subjects were nonsmokers and no one was taking an angiotensin-converting enzyme inhibitor. Methacholine inhalational challenge was negative in all. Treatment directed at postnasal drip syndrome failed to resolve chronic cough. Twenty-four hour, double-probe, esophageal pH monitoring with event recorders was performed in all subjects. Significantly more gastroesophageal reflux–induced coughs were recorded from the distal esophagus than from the proximal esophagus. Two subjects who were found to have distal gastroesophageal reflux–induced cough failed to cough during reflux events in the proximal esophagus. Finally, pH monitoring failed to detect proximal gastroesophageal reflux in one individual with cough induced by distal esophageal reflux. Schnatz et al. (21), using dual-probe esophageal pH monitoring, also found that chronic cough could be induced by distal esophageal reflux alone and that symptoms responded to therapy directed at gastroesophageal reflux. Ing and colleagues (64) studied the role of distal esophageal acid exposure in 22 subjects with chronic cough and gastroesophageal reflux determined by esophageal pH monitoring and 12 matched controls. In a double-blind controlled fashion, 0.1 N HCl and 0.9% saline were instilled in random order into the esophagi of all subjects. Coughs were monitored using a microphone and computer analysis. Study subjects had statistically significant more coughs (36.5) during acid infusion compared to controls (0.0). The inhibition of acid-induced cough was then evaluated. Repeat acid perfusion was performed 15 minutes after the application of 4% lignocaine or ipratropium bromide. Subjects who received lignocaine had a significant reduction in the frequency of cough, while individuals who received the instilled ipratropium bromide had no significant reduction in any cough parameter. However, a significant reduction in cough frequency was observed when ipratropium bromide was administered by the inhalational route. The authors concluded that these observations provided indirect evidence of the tracheobronchialesophageal reflex since instilled lignocaine acted locally, presumably on the afferent limb of the cough reflex, while inhaled ipratropium inhibited the efferent limb in suppressing cough. Gastroesophageal reflux may lower the cough threshold. Ferrari and coworkers (55) studied 29 patients with digestive symptoms but no cough using esophageal manometry and pH monitoring. Fifteen subjects were thought to be refluxers based upon abnormally high total esophageal acid-exposure time. The

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cough threshold was then evaluated in both refluxers and nonrefluxers using methacholine and capsaicin inhalational challenge. The dosage of methacholine causing a 20% fall in the forced expiratory volume in 1 second (provocative dose or PD20) was similar in refluxers and nonrefluxers. Capsaicin’s ability to cause cough was evaluated in a similar fashion. The concentration of inhaled capsaicin in a dosimeter was gradually increased until five coughs were produced (PD5) or the maximal dosage of capsaicin was reached. Refluxers were found to have a much lower PD5 (0.51 nmol) than nonrefluxers (19.8 nmol). Based upon these observations, the investigators concluded that acid reflux appears to lower the cough threshold. There is also a considerable amount of data in asthmatics supporting the existence of the tracheobronchial-esophageal reflex. Intraesophageal perfusion of 0.1 N HCL has been shown to decrease vital capacity and the forced expiratory volume in one second in asthmatics (56,57). Esophageal acid instillation also has been shown to increase respiratory airway resistance and the degree of bronchoconstriction produced by methacholine provocation testing in asthmatics (58,59). Similar observations have been seen in anesthetized cats (60). Increased airway resistance following intraesophageal acid perfusion has been seen in dogs and can be abolished by vagotomy (61). It should be noted, however, that gastric acid may not be the only stimulus of afferent receptors within the esophagus. Intraesophageal perfusion of acid has not reliably produced cough in patients with proven gastroesophageal reflux-induced cough (20,42). Irwin et al. observed cough induced by alkaline reflux events (20). In a study of 29 patients with digestive symptoms but without respiratory complaints, acid reflux was evaluated using pH monitoring and esophageal manometry (55). Acid reflux was observed to induce cough in only one individual. Furthermore, the severity of gastroesophageal acid reflux in individuals with enhanced sensitivity to capsaicin but free of respiratory symptoms was similar to that reported by others where gastroesophageal reflux was found to cause cough (19,42,62). Other constituents of gastric secretions, particularly pepsin and trypsin, have been shown in animal models to be more damaging to the esophageal mucosa than acid (63,64). Mechanical forces may also be important triggers of afferent receptors within the esophagus. Mansfield and coworker (61) observed that, in addition to esophageal acid instillation, esophageal distention by balloon inflation increased airway resistance in dogs. Again, this observation did not occur once the animals were vagotomized. Further studies are needed to elucidate the exact mediators of gastroesophageal reflux–induced cough. Some researchers believe that reflux is provoked by a pumping effect imposed on the stomach by exaggerated respiratory efforts in patients with respiratory disease, while others have postulated the existence of a positive feedback cycle between cough and gastroesophageal reflux (41,54,65–68). Allen and col-

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leagues (69) demonstrated that reflux is unlikely to be provoked by respiratory efforts or that cough induces further reflux. Inspiratory loading during tidal breathing failed to induce reflux in patients with reflux disease and in control subjects. Furthermore, inspiratory loading and coughing appeared to terminate reflux events. Increases in transdiaphragmatic pressure during coughing have not been shown to promote gastroesophageal reflux in patients with normal basal lower esophageal sphincter tone (41). Intraesophageal pH is typically around 7 (70). Johnson and colleagues (71) defined reflux as an intraesophageal pH less than 4. Gastroesophageal reflux is a normal physiologic process. It occurs in every individual many times each day without causing signs or symptoms of injury. Physiologic reflux is defined as rapidly cleared upright reflux episodes occurring primarily after meals (70,71). The total time at pH ⬍ 4, sometimes referred to as the acid-exposure time, is felt to be the single best indicator of abnormal reflux (70–74). The upper limit of normal for acid-exposure time in the distal esophagus is felt to be between 5 and 7% (72,74,75). Gastroesophageal reflux becomes pathologic, however, when it produces symptoms or signs of injury within the digestive or respiratory tracts (76). In patients with chronic cough felt to be secondary to gastroesophageal reflux, the number and duration of reflux episodes, total acid-exposure time, and the temporal relationship between reflux episodes and cough are important considerations in establishing causality. Ing et al. (19) observed that patients with reflux-induced cough experienced more reflux events per 24 hours and longer reflux episodes. Furthermore, significantly more time was spent with an intraesophageal pH ⬍ 4.0 in patients with gastroesophageal reflux–induced cough than in control subjects. Irwin et al. (42) observed that the number of coughs was significantly correlated with the number of refluxes, the longest reflux, and the percentage of time that the intraesophageal pH was ⬍4.0. These findings were duplicated in a study of 30 patients with cough thought to be due to gastroesophageal reflux (62). These characteristics, however, are not universal in patients with reflux-induced cough. Patients with proven gastroesophageal reflux–induced cough sometimes have a normal number of reflux events and percentage of time with an intraesophageal pH ⬍ 4.0 (20). In some patients, the only significant finding is a correlation between an episode of reflux and the initiation of cough (20). Gastroesophageal reflux should be considered as a potential cause of cough in patients with normal standard reflux parameters if a definite temporal relationship is observed (41). It should also be noted that gastroesophageal reflux may be the cause of cough even if the temporal correlation between reflux and cough episodes is low. In a study of 15 patients with chronic, unexplained cough, esophageal manometry and pH monitoring were used to evaluate the temporal relationship between reflux and cough episodes (77). Gastroesophageal reflux was found to precede coughing in only 9% of the total cough episodes.

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III. Clinical Presentation Cough due to gastroesophageal reflux does not have any unique qualities. The duration of cough due to gastroesophageal reflux can be quite variable. It is not uncommon for patients to present with cough that has been present for a number of years. In our study of the characteristics of cough (7), the mean duration of cough was 6.6 years with a range of 1 month to 44 years, while in two other studies of cough due to gastroesophageal reflux, the mean duration of cough was 33 and 39 months, respectively (20,42). Reflux-induced cough has varying degrees of sputum production. The spectrum and frequency of the causes of cough, based on the quantity of sputum production, were evaluated in our study of the predictive values of the character, timing, and complications of chronic cough (7). Of those subjects with refluxinduced cough, 50.7% had dry cough, while 15.9% had more than 60 ml per day of sputum. Smyrnios et al. (9) studied 71 patients who complained of cough productive of greater than 30 ml of sputum per day. Gastroesophageal reflux was the third most common cause of cough in this cohort and was the etiologic factor in 15% of patients overall. That gastroesophageal reflux can produce mucus, even in the absence of gross or microaspiration, should not come as a surprise since laboratory studies have demonstrated that gastric irritation is capable of causing a vagally mediated increase in the secretion of tracheal mucus in cats (78). Furthermore, when gastroesophageal reflux results in aspiration syndromes, tracheobronchitis with fevers, wheezing, and purulent sputum production may develop (52). While it has been stated in the literature that nocturnal cough is typical of gastroesophageal reflux disease, this relation has not been seen consistently in detailed studies that have evaluated this issue (52,79). In fact, nocturnal cough has been found to occur as frequently in patients with gastroesophageal reflux as it does in individuals with asthma and postnasal drip–induced cough (7). In addition, Irwin et al. (42), using prolonged esophageal pH monitoring, demonstrated that cough due to gastroesophageal reflux most commonly occurs while patients are awake and upright. It is important to emphasize that symptoms suggestive of gastroesophageal reflux are frequently lacking in patients with reflux-induced cough, and their absence should not sway one away from considering reflux as a potential cause of cough. Ing and colleagues have reported that between 50 and 75% of patients with reflux-induced cough deny reflux symptoms (54,62). Irwin et al. (42) demonstrated that cough can be the only symptom of gastroesophageal reflux disease proven by 24-hour esophageal pH monitoring. Gastroesophageal reflux–induced cough, however, can be accompanied by prominent classic reflux symptoms such as heartburn, waterbrash, regurgita-

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tion, and sour taste (81). Furthermore, some individuals may present with refluxinduced cough and atypical symptoms such as chest pain, globus sensation intractable nausea, intermittent wheezing and stridor, dental erosion, hoarseness, and sore throat (52,81–86).

IV. Diagnosis A high degree of clinical suspicion must exist if one is to diagnose gastroesophageal reflux–induced cough. A carefully taken history is probably not helpful in diagnosing gastroesophageal reflux as the cause of cough. Our group evaluated the clinical utility of a carefully taken history and physical examination in predicting the cause of chronic cough (7). Eighty-eight patients with chronic cough were evaluated prospectively in a tertiary care, pulmonary, outpatient clinic that specializes in the diagnosis and treatment of chronic cough. Gastroesophageal reflux was determined to be the cause of cough in 40% of subjects. Patients were provided a fixed, alternative yes-or-no questionnaire that assessed the character, timing, and complications of cough. Descriptors included paroxysmal, honking, barking, postprandial, nocturnal, and associated with meals. No descriptor or characteristic of cough was found to be helpful in predicting the cause of cough. In addition, as previously stated, typical accompanying symptoms of gastroesophageal reflux are commonly absent (54,62). Air-contrast barium swallow has been employed widely in the diagnosis of gastroesophageal reflux. Traditionally, movement of barium from the stomach into the esophagus is considered diagnostic for gastroesophageal reflux (76). Cough is believed to be likely due to reflux when other, more common, causes of cough have been ruled out and there is evidence of reflux on barium esophagram (9,20). The precipitation of cough with reflux of barium into the esophagus is not required for the presumptive diagnosis of gastroesophageal reflux–induced cough. Hence, barium swallow only confirms the presence of reflux but does not establish the cause of the patient’s cough. In this setting, causality is established only when therapy for gastroesophageal reflux results in resolution of the patient’s cough. Upper gastrointestinal series have been shown to produce a high rate of false-positive and false-negative results. Several studies have demonstrated that approximately 20% of normal control subjects will have abnormal barium esophagrams (87,88). Irwin and colleagues have reported extensively on the reliability of barium swallow in diagnosing reflux-induced cough (9,10,20). The sensitivity and specificity of barium swallow in diagnosing gastroesophageal reflux–induced cough ranges from 48 to 92% and 42 to 76%, respectively. The clinical usefulness of barium esophagography in diagnosing cough in this clinical setting has been reported to be as low as 17% (9). Barium esophagography, however, may have a role as a noninvasive study when local anatomic disorders or

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complications of gastroesophageal reflux such as hiatal hernia, strictures, and ulcerations are suspected (76). Esophageal endoscopy is another diagnostic modality by which the presence of gastroesophageal reflux can be established. As is the case with barium swallow, endoscopy only confirms the presence of reflux but does not establish that reflux is the etiology of the patient’s cough. Again, causality is established retrospectively after a course of therapy for gastroesophageal reflux abolishes the cough. The sensitivity of esophageal endoscopy in diagnosing gastroesophageal reflux is limited to the presence of mucosal damage. Endoscopic and histologic mucosal changes are found in only 30–50% of individuals with symptomatic reflux (70,89–91). In one study of gastroesophageal reflux–induced cough (20), histologic evidence of esophagitis was found in only 25% of patients. Endoscopy, however, is very useful (and mandatory) in patients with longstanding reflux symptoms and in those with warning symptoms suggestive of malignant disease (92). The Bernstein test is another method of evaluating acid-related symptoms. This test is performed by instilling either 0.1 N HCl or normal saline into the esophagus and is considered positive when symptoms are reproduced with the instillation of acid but not saline. The reported sensitivity of the Bernstein test for gastroesophageal reflux disease has been reported to average around 78–80% (76,93,94). The test’s sensitivity, however, appears to be much lower (7–27%) when attempting to ascertain the cause of atypical chest pain (95,96). Similar disappointing results have been obtained when attempting to reproduce cough and nausea in patients with proven gastroesophageal reflux–induced cough and nausea (20,42,82). Prolonged esophageal pH monitoring appears to be the single best test in screening for gastroesophageal reflux disease. Esophageal pH monitoring has a sensitivity and specificity of approximately 96% in patients with typical reflux symptoms (70,93,97,98). The distal pH electrode is usually placed 5–6 cm above the gastroesophageal junction (5,42,70). A second, proximal pH sensor can be placed in the hypopharynx or proximal esophagus at least 2 cm above the thoracic inlet (5,42,99). Two types of data are obtained from esophageal pH monitoring. First, intraesophageal pH is recorded in real-time fashion. Second, symptoms are time-logged using an event marker and diary. Data from the event marker, diary, and pH probes can then be evaluated for temporal relations between symptoms and changes in intraesophageal pH. Ambulatory esophageal pH monitoring appears to have its greatest utility in diagnosing atypical symptoms caused by gastroesophageal reflux. Furthermore, the American College of Gastroenterology has stated that patients with pulmonary symptoms may benefit from ambulatory pH monitoring (93). The utility of pH-metry in evaluating unexplained pulmonary symptoms has now been demonstrated by a number of investigators (5,7,16,19–21,24,28,42,54,77,85,99). Esophageal pH monitoring is felt to be the

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‘‘gold standard’’ in the evaluation of reflux-induced cough and may be the only method of diagnosing gastroesophageal reflux in up to 32% of patients with reflux-induced cough (5). The sensitivity and specificity of esophageal pH monitoring in diagnosing reflux-induced cough are felt to approximate 92% (20). The importance of using a dual-probe esophageal pH-monitoring system cannot be overemphasized because both proximal as well as distal reflux events can trigger cough. In a study of gastroesophageal reflux and cough, Vaezi and Richter (100) found a statistically significant increase in the number of distal, supine, and upright reflux events, as well as proximal reflux episodes in the upright position in patients with GER-related cough compared to patients with cough due to other causes (Figs. 2, 3) The importance of proximal reflux events was further documented by Shaker and colleagues (101) in a study of the esophageal distribution of gastric acid refluxate in patients with reflux-induced laryngitis. These investi-

Figure 2 Mean distal esophageal acid reflux values (upright and supine positions) for patients with cough due to gastroesophageal reflux (GER), pulmonary/otorhinolaryngologic (ORL) causes, and unknown causes. Broken lines indicates upper limits of normal. (NS ⫽ not significant.) Reprinted with permission from Ref. 100.

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Figure 3 Mean proximal esophageal acid reflux values (upright and supine positions) for patients with cough due to gastroesophageal reflux (GER), pulmonary/ otorhinolaryngologic (ORL) causes, and unknown causes. Broken lines indicate upper limits of normal (NS ⫽ not significant). Reprinted with permission from Ref. 100.

gators found that more proximal reflux events occurred in patients with laryngitis than in controls (Table 1). As previously stated, the temporal relationships between reflux episodes and symptoms, the number and duration of reflux events, and the total acid-exposure time are felt to be important diagnostic parameters obtained from esophageal pH monitoring. More specifically, gastroesophageal reflux is felt to be the cause of cough based upon a pH-monitoring study when the following indicators are also present: (a) reflux events appear to induce cough, (b) there are more than four reflux events lasting more than 4 minutes, (c) percent of time that pH is ⬍4.0 is longer than 4.4%, and (d) the number of reflux events is greater than 50 (20,80). Caution must be used, however, in attempting to establish a causal relationship between reflux and cough when the total number or duration of reflux events is extremely high and only a few reflux episodes are temporally related to coughing. Any temporal relationship in this particular set-

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Table 1 Comparison of Regional Distribution of Refluxed Gastric Acid Between Distal and Proximal Esophageal and Pharyngeal Sites Groups

Ratio Total study duration Proximal/distal Pharynx/proximal Upright duration Proximal/distal Pharynx/proximal Supine duration Proximal/distal Pharynx/proximal

Normal controls (%)

ENT controls (%)

GERD (%)

Laryngitis (%)

23 ⫾ 6.5 1.2 ⫾ 1.0

16 ⫾ 6.8 0

32 ⫾ 5.4 0.2 ⫾ 0.21

51 ⫾ 7.0a 30 ⫾ 10a

1.9 ⫾ 5.6 1.0 ⫾ 0.006

11 ⫾ 5.6 0

27 ⫾ 5.5 2.0 ⫾ 0.05

49 ⫾ 7.4b 30 ⫾ 14a

11 ⫾ 7.0 0

28 ⫹ 12 0

30 ⫹ 7.0 0.1 ⫾ 0.1

25 ⫹ 7.6 13 ⫾ 8.0a

Note: Results are expressed as mean ⫾ SE. a p ⬍ 0.05, laryngitis vs. all other groups. b p ⬍ 0.05, laryngitis vs. ENT and normal controls. Source: Ref. 101.

ting may be coincidental, and, as a result, one can only be certain that a pHmonitoring study is truly positive if specific antireflux therapy results in resolution of cough. Finally, an empiric trial of antireflux therapy is an alternative and reasonable diagnostic tool. This approach is particularly attractive when esophageal pH monitoring is not available. If an empiric therapeutic trial is chosen, it should be noted that treatment should be continued for 3–4 months before one can declare treatment failure, based upon observations from four prospective studies on gastroesophageal reflux–induced cough (5,42). However, laboratory confirmation of the presence of gastroesophageal reflux, preferably by pH monitoring, should be obtained whenever possible for two major reasons. First, patient acceptance of reflux-induced cough in the absence of laboratory confirmation of the presence of underlying reflux can be difficult, especially if typical gastrointestinal symptoms of gastroesophageal reflux are absent. Second, since the negative predictive value of pH-metry is high, documenting the absence of reflux prevents the use of unnecessary, costly, and prolonged therapeutic trials and expedites the diagnostic process. In the appropriate clinical setting, that is, a nonsmoker with a normal chest roentgenogram who is not using an angiotensin-converting enzyme inhibitor and in whom asthma and postnasal drip have been excluded as the cause of chronic

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cough, gastroesophageal reflux should be considered the most likely etiology of the patient’s cough (5–9,13,16). Several studies have confirmed that cough often can be caused by multiple, simultaneously contributing factors (4–9,13,14,17, 102). Given this observation, gastroesophageal reflux also should be considered as a cause of cough in individuals in whom specific treatment directed at asthma and postnasal drip results in partial improvement. In this setting, esophageal pH monitoring is indicated to assess for the possibility that gastroesophageal reflux also may be contributing to the patient’s cough.

V.

Treatment

The management of gastroesophageal reflux–induced cough involves both lifestyle modifications and pharmacotherapy. Occasionally, under certain circumstances, surgical intervention is needed. It is important to note that the cough caused by gastroesophageal reflux tends to respond very slowly to therapy, and, as a result, a prolonged course of therapy is required. The duration of therapy may be as long as 179 ⫾ 205 days before a significant response to treatment is obtained (5). The concept of lifestyle modifications stresses the avoidance of foods, drinks, and practices known to make reflux worse and is the mainstay of therapy for reflux-induced cough. While lifestyle modifications have not been systematically studied as monotherapy for gastroesophageal reflux–induced cough, they have been evaluated in combination with H2 blockers and/or prokinetic agents (5,20,24,42). Physiologic studies have demonstrated that reduction of fat intake, elevation of the head of the bed, and avoidance of food and drink 3 hours prior to recumbancy decrease distal gastroesophageal reflux (93,103–106). It is recommended that patients be placed on a diet which is high in protein and low in fat (80). Total daily fat intake should not exceed 45 grams. Chocolate, peppermint and spearmint, onions, coffee, tea, cola beverages, and citric fruit juices should be avoided because these substances have been shown to promote gastroesophageal reflux (76,107–109). Smoking cessation is also important because smoking has been shown to provoke acid reflux and may reduce lower esophageal sphincter pressure (110). H2-receptor antagonists most commonly have been employed in the treatment of gastroesophageal reflux–induced cough (5,7,20,24,42). These agents work by decreasing acid secretion and gastric volume by inhibiting histamine-2 receptors. In gastroesophageal reflux disease, 60% (range 32–82%) of patients experience symptom improvement with the use of H2 antagonists (93). Response rates of reflux-induced cough treated with H2 blockers, either alone or in combination with prokinetic agents, range between 70 and 84% (5,24). It should also be noted that no one H2 receptor antagonist has been shown to be superior in the

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management of reflux-induced cough. Given the extensive data on the use of these agents, histamine-2 receptor antagonists should be considered first-line therapy, along with lifestyle modifications, for the treatment of reflux-induced cough. The proton pump inhibitors have been shown to be effective in the treatment of gastroesophageal reflux disease. These agents have been shown to be more efficacious than H2 antagonists in healing erosive esophagitis and alleviating the symptoms of gastroesophageal reflux (111–113). It is important to note that there is little data on the use of proton pump inhibitors in treating gastroesophageal reflux–induced cough. Kamel and colleagues (112) reported that omeprazole may be effective in treating acid laryngitis. In another study, Harding et al. (113) investigated the role of omeprazole in 30 asthmatics with gastroesophageal reflux documented by esophageal pH probe monitoring. Patients were started on 20 mg of omeprazole per day, and the dose was titrated until acid suppression was demonstrated by esophageal pH monitoring. Once acid suppression had been attained, subjects were then treated with the adjusted dose of omeprazole for 3 months. These investigators found that at the end of the 3-month trial, omeprazole improved asthma symptoms and/or peak expiratory flow rates by ⬎20% in 73% of subjects. Depla et al. (114) reported a case where a 25-year-old male with severe nocturnal asthma who had failed a course of high-dose ranitidine experienced a dramatic improvement in asthma symptoms after treatment with omeprazole was instituted. In a double-blind placebo crossover study by Ford and colleagues (115), omeprazole failed to improve asthma symptoms and peak expiratory flow rates in 11 asthmatics. It should be noted, however, that, unlike the study by Harding et al. (113), where subjects were treated with omeprazole for 3 months, Ford et al. (115) treated patients for only 4 weeks. This observation suggests that the duration of therapy with proton pump inhibitors, as with other forms of therapy for gastroesophageal reflux–induced cough, may need to be prolonged as well, i.e., 3 months or longer. Until further data on the efficacy of proton pump inhibitors in the treatment of reflux-induced cough is obtained, H2 antagonists should be considered as first-line therapy. Prokinetic agents, such as metoclopramide and cisapride, work by increasing lower esophageal sphincter pressure and gastric emptying. These agents, in combination with H2 blockers, are useful in the treatment of reflux-induced cough. In a study of 20 patients with reflux-induced cough, metoclopramide, in combination with a H2 blocker and antireflux diet, was successful in stopping cough in 70% of subjects (24). Combination therapy with a H2 antagonist and cisapride has also been shown to be effective at ameliorating asthma symptoms in asthmatics with gastroesophageal reflux (116). Prokinetic agents may also be useful as monotherapy for reflux-induced cough. Most of the studies that have used a prokinetic agent alone have been performed in children. Saye and Forget

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(117) studied 19 children with reflux-associated bronchopulmonary disease. Subjects were treated with cisapride 0.3 mg/kg three times a day for 1 month. Esophageal pH monitoring was performed before and at the end of the treatment period. Of the 13 children with nocturnal cough fits, 12 experienced complete resolution of nocturnal coughing by the completion of the treatment period. Furthermore, these investigators demonstrated that cisapride significantly reduces the percentage of the total time the pH was ⬍4, the duration of the longest reflux event, and the duration of reflux at night. Similar results were obtained in a study of 38 children with severe chronic pulmonary disease, including chronic cough (118). Twenty-four subjects were found to have abnormal gastroesophageal reflux by pH monitoring. These children were then treated with cisapride 0.3 mg/kg for a total of 6 months. Cisapride was effective at producing resolution of respiratory symptoms in 82% of subjects. The combination of a prokinetic agent and a proton pump inhibitor may also be effective in the management of reflux-associated pulmonary symptoms. Vigneri et al. (119) demonstrated that omeprazole in combination with cisapride is more effective than ranitidine and cisapride in the maintenance treatment of reflux esophagitis. It is important to note that until studies that specifically evaluate the efficacy of prokinetic agents and/or proton pump inhibitors either alone or in combination are completed, H2 antagonists, with or without a prokinetic agent, and behavior modification should be considered firstline therapy for the medical management of gastroesophageal reflux–induced cough. Nissen’s and Belsey’s fundoplications and Hill’s posterior gastroplexy are surgical procedures that can be used in cases of refractory gastroesophageal reflux (76). The superiority of antireflux surgery over standard medical therapy in preventing relapse of the signs and symptoms of gastroesophageal reflux is well established (120,121). A number of studies have evaluated the efficacy of antireflux surgery in the management of reflux-associated respiratory symptoms (122– 126). In a study of 13 patients with symptomatic asthma and chronic cough who responded to H2 antagonists, respiratory symptoms were controlled in 11 subjects following antireflux surgery (121). Lomasney (124) produced relief of respiratory symptoms, including cough, in 74% of 129 consecutive patients who underwent antireflux surgery for respiratory complaints associated with gastroesophageal reflux. DeMeester (123) has suggested that only those patients with normal esophageal motility are likely to benefit from antireflux surgery to control respiratory symptoms. The efficacy of fundoplication in children with reflux-induced respiratory disease is also well established (125,126). Surgical intervention is indicated when there are gastrointestinal complications of gastroesophageal reflux such as stricture, hemorrhage, and Barrett’s esophagus despite maximum medical therapy (65,76). Fundoplication should also be considered when refractory gastroesophageal reflux results in ongoing damage to the respiratory system or if persistent

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coughing adversely affects one’s lifestyle or poses a significant risk of injury. Puetz and Vakil (127) reported a case of refractory reflux-induced cough that resulted in frequent cough-induced syncope. Nissen fundoplication resulted in resolution of both cough and syncope. In another study, four patients with refractory reflux-induced cough who underwent fundoplication experienced total resolution of cough 3 months after surgery (24). Recurrent aspiration with resultant pneumonia, bronchiectasis, and interstitial fibrosis, despite maximum medical therapy, also should be considered an indication for surgery.

VI. Conclusion Gastroesophageal reflux is a well-known cause of chronic cough. Reflux-induced cough is thought to occur either by aspiration or stimulation of the tracheobronchial-esophageal reflex. Symptoms of gastroesophageal reflux, such as heartburn, are frequently absent in patients with reflux-induced cough. The single best test for the diagnosis of reflux-induced cough is esophageal pH monitoring. Lifestyle modifications and H2 antagonists, sometimes in combination with a prokinetic agent, are the mainstay of treatment for cough due to gastroesophageal reflux. If complications develop, surgical intervention is sometimes warranted.

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6 The Prevalence of GERD in Asthma

STEPHEN J. SONTAG Veterans Affairs Hospital Hines, Illinois and Loyola University Stritch School of Medicine Maywood, Illinois

And God formed the human, of dust from the soil And blew into his nostrils the breath of life And the human became a living being. Genesis 2: 7 (1)

According to the Hebrew Bible, the human body was first constructed, then life was added by the acquisition of Holy breath. And so began the cycle of respirations. It was immediately clear, however, that the respirations could be sustained only by energy. And so from a Garden called Eden came the source of that energy—food. There was life and there was the source of life . . . and there was asthma and GER. I. Introduction The relationship between gastroesophageal reflux (GER) and asthma has been pondered since the beginning of time. We are not told whether Adam feared the first night in the garden because he had never before seen darkness or because he was worried about nocturnal wheezing. Readers of Genesis are left to their own interpretation. In time, great thinkers began to use food for certain medicinal 115

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purposes. In the Talmud (the vast collection of third- to sixth-century commentaries on the Hebrew Bible), the treatment for unwanted pulmonary symptoms usually involved some type of food. Coughing was treated with a fish oil drink (2), and asthma was treated with three wheat cakes soaked in honey followed by a drink of undiluted wine (3). Meanwhile, the fifth-century Roman physician Aurelianus Caelius, who was considered second only to Galen in the line of Greco-Roman physicians, offered detailed descriptions of night-time wheezing and noted the frequent nocturnal occurrence of asthma attacks (4). By the twelfth century, the great physician-philosopher, Moses Maimonides, strongly warned against overeating (5). Writing of an association between eating, lying down, and wheezing, Maimonides suggested in his Treatise on Asthma that sleep was dangerous during an attack: One should not sleep face downwards, nor on one’s back, but lying on the side; at the beginning, on the left side, and the close of one’s rest, on the right side. One should not go to sleep immediately after a meal, but only when three or four hours have elapsed. One should not sleep during the day.

During the eighteenth century, Nicholas Rosen von Rosenstein, the First Physician to His Swedish Majesty, discussed in his 1776 textbook The Diseases of Children and Their Remedies what he terms ‘‘the stomachic cough’’ of children: ‘‘Such a cough is caused by the natural proclivity of children to ingest huge quantities of disgusting food, that cannot be digested or changed as it ought’’ (6). Twenty-six years later, in his 1802 textbook The History and Cure of Diseases, William Heberden wrote, ‘‘in most persons, the breath is shorter and more difficult after a meal’’ (7). Almost a century later, in 1892, Sir William Osler published The Principles and Practice of Medicine in which he prepared for the twentieth century with an emphasis on eating habits: ‘‘Diet, too has an important influence and in persons subject to this disease severe paroxysms may be induced by overloading the stomach, or by taking certain articles of food’’ (8). Osler also suggested that particular attention be paid to the diet of the asthmatic: ‘‘A rule of which experience generally compels them to make is to take the heavy meal in the early part of the day and not retire to bed before gastric digestion is completed.’’ Despite the emphasis on diet and the strong references to a relationship between food, eating habits, and asthma, the GER/asthma concept remained difficult to swallow. For the next 50 years, only a few scattered wheezes were heard amidst the competing voices of subspecialty medicine’s bellowing burps and clamoring coughs. One of these scattered wheezes was G. W. Bray, who in 1934, at the height of the world depression, reported that dietary indiscretion in some patients could lead to asthmatic attacks (9). Bray’s comments, however, went relatively unnoticed until Belsey, in a review on pulmonary complications of esophageal disease, reported that patients with GER were liable to severe, pro-

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gressive, and disabling pulmonary damage (10). Within 2 years, J. H. Kennedy aroused not only the medical community’s hearts and minds, but its guts and lungs as well by suggesting that ‘‘silent’’ GER may be an important but poorly recognized cause of pulmonary complications (11). In 1967 Urschel and Paulson reported their experience in a highly selected population referred for repair of hiatal hernia (12). Figure 1 shows the results of their 5-year experience (1961– 1966) in 636 patients, ranging in age from 7 months to 94 years, who were referred for surgical correction of GER. Thirty-nine percent had classic reflux symptoms consisting of heartburn, indigestion, and postural aggravation without respiratory symptoms, 45% had both reflux symptoms and respiratory symptoms, and 16% had respiratory symptoms only. Thus, more than 60% of these patients, who were being referred for surgery to correct a gastroesophageal abnormality, actually had respiratory symptoms. Within a year of Urschel’s publication, Cherry and Margulies vocalized their findings and reported that laryngeal contact ulcers, as well as other abnormalities of the voice box, might be a result of chronic GER (13). By the 1970s, the stage had been set for serious and meaningful research on the relationship between GER and asthma. In the ensuing 27 years, investigators fondled the GER/asthma concept as if they were trying to atone for the previous

Figure 1 Symptoms in patients referred for antireflux surgery.

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2000 years of neglect. Indeed, a MEDLINE search using the terms GER and asthma revealed no fewer than 177 English language publications between 1966 and 1997. Figure 2 shows the types of publications in both the adult and pediatric literature. Of the 177 articles published, half were actual studies in which some type of diagnostic procedure or intervention was undertaken, and almost 80% were published in the adult literature. Indeed, the widespread belief that the GERasthma relationship pertains mainly to the pediatric, not the adult, population has no basis in fact. Figure 3 shows the percentage of adult and pediatric publications for each 5-year period since 1966. From 1966 to 1970 there were virtually no pediatric publications. From 1971 to 1985 the articles in the pediatric literature remained at approximately 33–42% of the total. At no time, however, did the number of pediatric articles surpass the number of adult articles. In fact, for every 5-year period, the number of publications in the adult literature was numerically greater than that in the pediatric literature. The burst of enthusiasm among pediatric investigators from 1971 to 1985 was followed by a 12-year wane that continues to the current day.

Figure 2 The GER/asthma relationship: types of publications (1966–1997).

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Figure 3 The GER/asthma relationship: adult vs. pediatric publications (1966–1997).

In general, the number of GER/asthma publications appears to be on the increase. Figure 4 shows the incidence of publications for each 5-year period. The average number of publications increases dramatically each year from 1980 to 1985 and then modestly for the next decade. The number of review articles parallels the number of total publications. Interestingly, in the 18-month period from January 1996 through June 1997, there was approximately one review article for every two publications. II. Coexistence Numerous authors have studied potential GER-induced asthma mechanisms and reported on the coexistence of GER and asthma in both children (14–16) and adults (17–20). Although these studies strongly suggest a dependent relationship between GER and asthma, they were designed for the most part to clarify the mechanism by which GER might cause asthma. They were not designed to determine the prevalence of GER in the asthmatic population.

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Figure 4 The GER/asthma relationship: incidence of publications (1996–1997).

III. Definitions Of the 177 articles published, we identified 18 (7 children, 11 adult) with sufficient information from which prevalence data could be extracted. In general, the definitions of asthma were uniform, but the definitions of GER differed considerably. For the most part, however, the definition of GER did reflect the presence of pathological reflux. The terms prevalence and incidence were often confused and used interchangeably. We took the liberty of switching the terms when incidence was mistakenly used for prevalence. A.

Asthma

Most of the prevalence studies originate from pulmonary referral centers. The definition of asthma was not always defined in the reports. The occurrence of wheezing and reversible airway disease, as well as the requirement for classical asthmatic therapy, indicates that almost all if not all of the patients enrolled in these studies truly met the accepted criteria for asthma. A few of the studies, reported by groups with a focus in gastroenterology, actually documented the asthmatic state with the methacholine bronchoprovocation test and/or the measurement of airway reversibility after bronchodilator administration.

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B. GER Disease

The prevalence studies varied in their methods for determining the presence or absence of GER. The documentation of GER was based on either direct or indirect evidence. The number of methods used to document the occurrence of GER disease by any given center varied from 1 to 5. Table 1 shows the methods used to document the presence of GER. C. Prevalence and Incidence

The term incidence, which is one of the most misused terms in the medical literature today (21), is often used erroneously in place of prevalence. Indeed, a number of the GER/asthma publications unintentionally used the word incidence in the title, although they actually reported the prevalence. In the clinical setting, for example, the term incidence refers to the number of new cases of a disease (e.g., GER) that surface in a defined population (e.g., asthmatics) over a specific period (e.g., 10 years) of time (22). Since incidence is always expressed in terms of time (cases per year), the true incidence of GER symptoms in asthma could be determined only by following a large group of asthmatics who do not now have GER and identifying those that develop GER over time. The total absence of data on the true incidence of GER in asthma, therefore, is understandable, since determining incidence would be an undertaking of almost impossible dimensions. Prevalence, on the other hand, refers to the number of cases of a disease (e.g., GER) that exist at a specific period of time (today) in a defined population (e.g., asthmatics) (22). Since prevalence is expressed in terms of current numbers (cases per thousand people), the true prevalence of GER symptoms in asthma could be determined by identifying a large group of asthmatics and identifying those who have GER now. Determining the prevalence is a feasible task and within the reach of many academic centers. It is not difficult to understand, therefore, why all the epidemiological data on the relationship between GER and

Table 1 Methods Used to Document the Presence of GER Direct Evidence

Indirect Evidence

Short-duration esophageal pH testing Long-duration (24-h) esophageal pH testing Esophagoscopy Cine barium radiography Scintigraphy

Symptoms of GER Esophageal manometry and motility Presence of hiatal hernia on standard barium radiography

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Table 2 Differences Between Incidence and Prevalence Incidence

Prevalence

Define a group of asthmatics Select those without GER Follow for years Identify those that develop GER each year Example: 10 new GER cases/yr/1000 asthmatics followed

Define a group of asthmatics Select entire group Workup now Identify those that have GER now Example: 80 current GER cases/1000 asthmatics now

asthma are limited to reporting the prevalence rates. Table 2 demonstrates the major differences between prevalence and incidence. The differences between incidence and prevalence are important to both the physician and the patient, with the patient usually interested in the incidence. For example, an asthmatic patient might be less interested in knowing the number of patients who have GER at any particular moment (the prevalence rate), and more interested in knowing how frequently asthmatics like himself, who do not currently have GER, will develop GER at some point in the future (incidence rate). IV. Study Design and Sampling Procedures Accurate prevalence studies rely on accurate recruitment of patients. For data to be meaningful and generally applicable, the population of asthmatics studied should represent the population of asthmatics at large. Most of the epidemiological studies originate in large academic teaching hospitals. Since teaching hospitals and clinics are dependent on the referral of patients for treatment, the studies that report on prevalence rates are subject to two types of selection bias: subject selection bias and spectrum bias (23–26). In subject selection bias, patients are unintentionally selected who have both asthma and GER or who have neither asthma nor GER. The importance of such selection bias cannot be overemphasized since the bias (although unintentional) can produce seriously misleading results. In the available studies on prevalence rates, the difficulty in recruiting consecutive patients was clearly an issue. Indeed, selection bias, which could not be avoided, remains a real problem in the interpretation of the results. Spectrum bias, the second type of bias, may occur when more patients with GER than without GER volunteer for a study. Again, such a bias may be unintentional on the part of both the investigators and patients. Spectrum bias, however, rather than create an association when none exists, is more likely to

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lessen associations between variables. Thus, in studies reporting an association between GER and asthma, the presence of spectrum bias is more likely to lessen that association. Selection bias and spectrum bias are considered common problems in clinical samples. A third type of bias is the hidden bias of Berkson’s fallacy—the possibility of spurious associations between diseases (GER associated with asthma) in specific studies. Because of the nature of most referral centers, it is likely that the results of prevalence studies do show Berkson’s fallacy, which states that the interplay of differential admission rates ‘‘from an underlying population to a particular study group’’ can result in an artificial association in the study group (27). For instance, many patients are likely to have GER and many patients are likely to have asthma. In tertiary hospitals and referral centers, therefore, GER and asthma are likely to occur together in the same patient merely by chance. Such an occurrence may represent a spurious association between GER and asthma. Unfortunately, the nature of tertiary hospitals and referral centers is such that Berkson’s fallacy is difficult to avoid. In a few of the 18 studies, the investigators actually attempted to eliminate bias from the study sample by confining the study to consecutive asthmatics and eliminating from the data any asthmatics who were referred for work-up because of gastrointestinal symptoms. Even in this population, however, Berkson’s fallacy could not entirely be ruled out.

V.

Prevalence of GERD in Adults with Asthma

A. GERD Defined as the Presence of Reflux Symptoms

Figure 5 shows the prevalence of GER symptoms in adult asthmatics in three studies with sufficient interpretable data. In the first study, Perrin-Foyalle et al. (28) found evidence of reflux symptoms in 65% of 150 consecutive asthmatics. In the second study, O’Connell et al. (29) reported that 72% of 189 consecutive asthmatics had heartburn. Almost half of the 189 had supine nocturnal heartburn, and 18% had nocturnal burning in the throat. In the third study, Field et al. (30) studied 109 asthmatics and 135 controls in a questionnaire-based, cross-sectional analytic study. Seventy-seven percent of the asthmatics had heartburn, 55% had regurgitation, and 24% had difficulty with swallowing; 37% of the group required at least one antireflux medication, and 41% during the prior week had refluxassociated respiratory symptoms. Pulmonary symptoms occurred significantly more frequently in the asthmatics than in the controls. The results of these three studies, which together comprise a group of 448 asthmatics from France, Canada, and the United States, are remarkedly similar. Taken as a group, 318 of the 443 patients had reflux symptoms, indicating that 72% of asthmatics have reflux symptoms. Despite some weaknesses in the pa-

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Figure 5 GER symptoms: prevalence in adult asthmatics.

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tient-selection methods in all three studies, these reports present the most reliable data in the medical literature on GER symptoms in consecutive asthmatics. B. GERD Defined as the Presence of Abnormal Acid Reflux

Figure 6 shows the prevalence of abnormal acid reflux in adult asthmatics in six studies comprising 527 patients from six centers in four countries (France, Chili, Great Britain, and United States). The prevalence of abnormal acid reflux, as determined by pH testing, ranged from 33 to 90% (31–36). In two of the studies (31,36), short-term acid reflux testing was used to determine the presence of GER. These studies were conducted in the 1980s before the availability of ambulatory 24-hour pH testing. The remaining four studies (32–35), comprising 365 patients, utilized ambulatory 24-hour pH testing to determine abnormal GER. In all six studies, recruitment of consecutive asthmatics was suboptimal in that all depended on referral centers to enroll their patients. Nevertheless, the studies represent the most reliable data found in the literature on pH testing and the prevalence of GER in asthma. When the results of these six studies are combined, 362 of the 527 (69%) enrolled patients had evidence of acid reflux, suggesting that up to 70% of asthmatics have GER as defined by abnormal acid pH testing. C. GERD Defined as the Presence of Esophageal Mucosal Damage

Figure 7 shows the prevalence of esophageal mucosal damage in adult asthmatics (37). Esophageal erosions or ulcerations as seen on endoscopy were present in 39% of consecutive asthmatics, and 13% had Barrett’s esophagus. In this study, Sontag et al. limited the recruitment to consecutive asthmatics who were referred for endoscopy in an approved study on the prevalence of GER abnormalities in consecutive asthmatics. The authors eliminated from their study any patients who were referred for workup because of gastrointestinal symptoms and who were not part of the consecutive asthmatic protocol. Thus, this study appears to be one of the few that reports the prevalence of GER as it relates to esophageal mucosal damage in consecutive asthmatics. D. GERD Defined as the Presence of Hiatal Hernia

Figure 8 shows three studies that used the presence of hiatal hernia as indirect evidence of the presence of GER (37–39). In the first study, Mays reported on 28 patients with severe asthma, 64% of whom had hiatus hernia and 46% of whom had barium reflux (38). These studies were criticized by Chernow and Castell (40) because of the lack of data demonstrating aspiration, the reliance on upper gastrointestinal series to determine GER, and the abnormally low prevalence of hiatus hernia and barium reflux in the control group. Despite the criticisms, however, they concluded that the postulated relationship between GER

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Figure 6 Abnormal acid reflux: prevalence in adult asthmatics.

and asthma most likely existed, but that it was premature to suggest cause and effect. In the second study, which included 15 patients with nocturnal asthma (39), Rodriguez-Villarrel reported a 73% prevalence rate of reflux based on a combination of barium x-ray studies, endoscopy, and technetium scintigraphy. In his report, 11 of 15 patients had abnormal barium x-rays, indicating a 73%

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Figure 7 Esophageal mucosal damage: prevalence in adult asthmatics.

prevalence rate of reflux in asthmatics. In the third study, Sontag et al. (37) showed that hiatal hernia was present in 58% of consecutively chosen asthmatics using predetermined endoscopic criteria for hiatal hernia and esophagitis. In this study, all endoscopies were performed by one of two endoscopists using the same criteria for esophageal mucosal disease and the presence of hiatal hernia. In asthmatics with esophagitis, the hiatal hernia occurred seven times more frequently than in asthmatics without esophagitis, indicating that hiatal hernia in asthmatics is associated with more severe esophageal disease. When all three studies are combined, the prevalence of GER as defined by abnormal barium reflux on fluoroscopy or the presence of a hiatal hernia was 50%.

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Figure 8 Hiatal hernia: prevalence in adult asthmatics.

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Figure 9 Abnormal reflux parameters: prevalence in consecutive adult asthmatics.

Taken together, the results of the retrospective studies, with their highly selected referral patterns, agree to a great extent with the results of the prospective epidemiological and cross-sectional studies, which clearly demonstrate that GER is highly prevalent in asthmatic patients. Figure 9 summarizes the three prospective studies, which are part of the 12 adult prevalent studies. Approximately 75% of the asthmatics have heartburn, and almost 20% awaken with nocturnal burning in the throat (29), 80% of consecutive asthmatics have pathologic acid GER in either the upright or supine position, and 75% have increased frequency of reflux episodes (34). In addition, almost 60% of consecutive asthmatics have hiatal hernias (37), almost 40% have esophageal mucosal damage from reflux (37), and 90% of asthmatics have either reflux symptoms or esophageal mucosal disease or abnormal acid reflux. These data strongly indicate that GER is highly prevalent in consecutive adult asthmatics. VI. Prevalence of GERD in Children with Asthma Figure 10 shows the prevalence of GER in child asthmatics (41–48). The eight studies, with a total of 783 patients, report prevalence rates of GER ranging from 47 to 64%, with a mean prevalence of 56%. Although these studies suffer from the same biases in selection process as the adult studies, they provide the most

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Figure 10

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Prevalence of GER in child asthmatics.

reliable data available. In the first study, which is a retrospective radiographic review of 54 children with unremitting asthma, Friedman reported a 48% prevalence rate of hiatal hernia (41). The prevalence rate was significantly higher than the 19% prevalence of hiatus hernias seen in the matched control group. Despite the well-known limitations of such retrospective radiographic reviews, the finding that almost 50% of the patients had a hiatal hernia is powerful evidence in support of the GER/asthma relationship. In the remaining seven studies (42–48), pH testing was used to define the presence of GER. Four of the studies used the short-term acid reflux test, while three used 24-hour esophageal pH testing. Taken together, 439 of the 783 child asthmatics had evidence of GER by either shortterm pH testing, long-term pH testing, or radiographic evidence of hiatal hernia. Thus, the GER prevalence rate of 56% in child asthmatics is similar to that reported in adult asthmatics.

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VII. Bronchodilators and GER in Asthmatics Support for the bronchodilator-induced GER concept comes from the numerous reports suggesting that asthma drug therapy relaxes the LES (14,49–51). Such an effect might be expected to promote GER, and asthmatics who require continuous bronchodilators would likely have more GER than those who do not require bronchodilators. In addition, bronchodilators might increase the risk of nocturnal asthma because of the loss of bronchodilating effect as the drug is eliminated throughout the night. Recent studies argue against the bronchodilator-induced GER concept. When asthmatic subjects who received bronchodilators were compared with those who did not receive bronchodilators, the reflux patterns were similar in both groups of asthmatics, indicating that the reflux was indeed intrinsic to the asthma and not a result of the bronchodilator therapy (34). Figure 11A shows the effect of asthma medications on the LES pressure, the total acid-contact time and the total reflux frequency in asthmatics taking bronchodilators and asthmatics taking

Figure 11 Effect of asthmatic medicine (A) on reflux parameters during the total 24-hour period; (B) on reflux frequency before and after eating and daytime and nighttime;(C) on acid contact time before and after eating and daytime and nighttime.

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no bronchodilators. Asthma medications clearly had no adverse effect on any of the three reflux parameters. Figures 11B and 11C demonstrate the effect of asthma medications, positions, and eating on the acid-contact time and frequency of reflux episodes in the same two groups of asthmatics—those receiving bronchodilators and those receiving no bronchodilators. The results clearly show that bronchodilators do not influence any of the GER parameters during the upright, supine, postprandial, or nonpostprandial periods (52). Asthmatic subjects receiving bronchodilators had no worse reflux than those not receiving bronchodilators, suggesting that bronchodilators do not promote postprandial or nocturnal GER. In summary, these 24-hour esophageal pH test results obtained during the normal, everyday positions in asthmatics receiving bronchodilator therapy and those receiving no bronchodilator therapy clearly suggest that GER is an intrinsic abnormality of asthma and not a result of bronchodilator-induced smooth muscle relaxation of the LES. VIII.

Incidence

The true incidence of GER in asthma is unknown. Since incidence (Table 2) can be determined only by following a large group of asthmatics who do not now have GER and identifying those that develop GER over time—a formidable task—the total absence of such data is understandable. Despite the lack of data on the incidence of GER, data on the prevalence raise an important issue: if the prevalence of GER in adult asthmatics is similar to the prevalence of GER in child asthmatics, what is the true incidence of GER? There are two explanations: (a) all the child asthmatics with GER grow up to become the adult asthmatics with GER (GER incidence ⫽ 0%), or (b) some child asthmatics with GER outgrow either the GER or the asthma; some adults with asthma develop GER while others with GER develop asthma (low, medium, or high incidence depending on the numbers). It is not unreasonable to suspect that some child asthmatics with GER become adult asthmatics with GER, or that children with GER who apparently ‘‘outgrow’’ their asthma later surface as adults with both asthma and GER. Since most children leave their pediatricians after adolescence, the information required to demonstrate continued asthma or GER is lost. As a result, the medical community sees two completely different populations, each with very similar conditions: childhood asthma with GER and adult asthma with GER. IX. The High Prevalence of GER and the GER/Asthma Theory If the high prevalence of GER in asthmatics is clinically relevant, it should be readily explainable. We suggest that the GER-asthma relationship consists of a

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self-propagating situation whereby reflux aggravates asthma, which in turn induces further reflux. In the early course of the disease, asthma may not be apparent, as aspiration-induced pulmonary symptoms may occur very infrequently— perhaps once or twice a year. With time, however, aspiration may become more frequent, and the pulmonary tree may become hypersensitive. The individual may be diagnosed as having asthma. The pulmonary tree becomes increasingly hypersensitive to a variety of stimuli. In such a scenario, the initial contribution of acid aspiration is no longer apparent, as the primary focus is on the asthma. In any individual patient, the emphasis may be placed on the GER if reflux symptoms predominate or on asthma if pulmonary symptoms predominate. The result is confusion over whether a patient with severe reflux has pulmonary symptoms or whether a patient with asthma has reflux symptoms. The unending debate about whether GER is a cause of the asthma or a result of the asthma becomes the focus of attention. At such a point, the question of whether GER exists in asthmatics or whether pulmonary symptoms exist in refluxers is irrelevant. For the individual patient, gastric contents refluxed into the pulmonary tree is an undesirable event, whether cause or effect, and it is up to the physician to determine how such events can be stopped. X.

Summary

Despite the 178 published studies on the relationship between GER and asthma, the true prevalence of GER in asthmatics must be estimated from fewer than 20 of the studies. The estimated prevalence is between 60–80% in adults and 50– 60% in children. The studies comprise highly selected referred populations that may not reflect the overall populations with asthma. Despite the limitations, however, we believe that the data reflect the general asthma population as much as can be expected. XI. Conclusion GER and asthma occur together frequently. The prevalence of GER is significantly increased both in children with asthma and in adults with asthma. Almost every study on the relationship between GER and asthma emphasizes the high prevalence of GER. A relationship between GER and asthma has been recognized for more than 2000 years, but has not been appreciated until recently—or perhaps it really once was appreciated, but lost to memory. It was King Solomon who once described in the Hebrew Book of Ecclesiastes the paradox of memory:

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Sontag Only that shall happen Which has happened, Only that occur Which has occurred; There is nothing new Beneath the sun! Sometimes there is a phenomenon of which they say, ‘‘Look, this one is new!’’ It occurred long since, in ages that went by before us. The earlier ones are not remembered; So too those that will occur later Will no more be remembered Than those that will occur at the very end. Ecclesiastes 1 :9–11

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

The Hebrew Bible. Genesis 2:7. The Talmud: Divrei Chayyim II, 52. The Talmud: Gittin, 69b. Aurelianus Caelius. In: De Morbis Acutis et Chronicis. Amsterdam: Wetstenland, 1709. Maimonides M. Treatise on asthma. In: Munter S, ed. Medical Writings of Moses Maimonides. Philadelphia: Lippincott, 1963. Nicholas Rosen von Rosenstein. On the cough of children. In: The Diseases of Children and Their Remedies. Birmingham, AL: LB Adams, 1776:183–190. Heberden W. Asthma. In: The History and Cure of Diseases. Birmingham, AL: LB Adams, 1802:62–69. Sir William Osler. Bronchial asthma. In: The Principles and Practice of Medicine. Birmingham, AL: LB Adams, 1776:497–503. Bray GW. Recent advances in the treatment of asthma and hay fever. Practitioner 1934; 34:368–371. Belsey R. The pulmonary complications of oesophageal disease. Br J Dis Chest 1960; 54:342–348. Kennedy JH. ‘‘Silent’’ gastroesophageal reflux: an important but little known cause of pulmonary complications. Dis Chest 1962; 42:42–45. Urschel HC, Paulson DL. Gastroesophageal reflux and hiatal hernia: complications and therapy. J Thorac Cardiovasc Surg 1967;53:21–32. Cherry J, Margulies SI. Contact ulcer of the larynx. Laryngoscope 1968; 78:1937– 1940. Berquist WE, et al. Quantitative gastroesophageal reflux and pulmonary function in

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asthmatic children and normal adults receiving placebo, theophylline, and metaproterenol sulfate therapy. J Allergy Clin Immunol 1984; 73:253–258. Davis RS, Larsen GL, Grunstein MM. Respiratory response to intraesophageal acid infusion in asthmatic children during sleep. J Allergy Clin Immunol 1983; 72:393– 398. Hughes DM, Spier S, Rivlin J, Levison H. Gastroesophageal reflux during sleep in asthmatic patients. J Pediatr 1983; 102:666–672. Overholt RH, Voorhees RJ. Esophageal reflux as a trigger in asthma. Dis Chest 1966; 49:464–466. Davis MV. Relationship between pulmonary disease, hiatal hernia, and gastroesophageal reflux. NY State J Med 1972; 72:935. Bretza J, Novey HS. GE reflux and asthma. West J Med 1979; 131:320. Perrin-Fayolle M, Gormand F, Braillon G, et al. Long-term results of surgical treatment for gastroesophageal reflux in asthmatic patients. Chest 1989; 96:40–45. Colton T. Statistics in Medicine. Boston: Little, Brown and Company, 1974: 46–47. Stedman’s Medical Dictionary. Baltimore: Williams & Wilkins, 1990. Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. N Engl J Med 1978; 299:926–930. Philbrick JT, Horowitz RI, Feinstein AR, Langou RA, Chandler JP. The limited spectrum of patients studied in exercise test research: analyzing the tip of the iceberg. JAMA 1982; 248:2467–2470. Feinstein AR. On blind men, elephants, spectrums, and controversies: lessons from rheumatic fever revisited. J Chronic Dis 1986; 39:337-342. Miller TQ, Turner CW, Tinsdale RS, Posavac EJ. Disease based spectrum bias in referred samples and the relationship between type A behavior and arteriosclerosis. J Clin Epidemiol 1988; 41:1139–1149. Berkson J. The statistical study of association between smoking and lung cancer. Mayo Clin Proc 1955; 30:319-324. Perrin-Foyalle M, Bel A, Kofman J, et al. Asthma and gastroesophageal reflux. Results of a survey of over 150 cases. Poumon Coeur 1980; 36:225–230. O’Connell S, Sontag SJ, Miller T, Kurucar C, Brand L, Reid S. Asthmatics have a high prevalence of reflux symptoms regardless of the use of bronchodilators. Gastroenterology 1990; 98(2):A97. Field SK, Underwood M, Brant R, Cowie RL. Prevalence of gastroesophageal reflux symptoms in asthma. Chest 1996; 109:316–322. Ducolone A, Vandevenne A, Jouin H, Grob JC, Coumaros D, Meyer C. Gastroesophageal reflux in patients with asthma and chronic bronchitis. Am Rev Respir Dis 1987; 135: 327–332. Nagel RA, Brown P, Perks WH, Wilson RSE, Kerr GD. Ambulatory pH monitoring of gastro-oesophageal reflux in ‘‘morning dipper’’ asthmatics. Br Med J 1988; 297: 1371–1373. Giudicelli R, Dupin B, Surpas P, Badier M, Charpin D, Lapicque JC, Fuentes P, Reboud E. Reflux gastro-oesophagien et manifestations respiratoires: attitute diagnostique, indications therapeutiques et resultats. Ann Chir 1990; 44:552–554. Sontag S, O’Connell S, Khandelwal S, Miller T, Nemchausky B, Serlovsky R,

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7 GERD, Airway Disease, and the Mechanisms of Interaction

SUSAN M. HARDING University of Alabama at Birmingham Birmingham, Alabama

Asthma is exacerbated by triggers that ignite an inflammatory response. There is an increased prevalence of gastroesophageal reflux in asthmatics and antireflux therapy can improve asthma outcome in selected patients. The mechanisms whereby esophageal acid induces bronchoconstriction have been examined extensively on a physiological basis. These mechanisms were first described by Sir William Osler, who stated that ‘‘attacks may be due to direct irritation of the bronchial mucosa or . . . indirectly, too, by reflex influences from stomach . . .’’ (1). These two mechanisms, microaspiration of esophageal acid into the upper airway and a vagally mediated reflex, are still thought to play a major role in acidinduced bronchoconstriction. However, to date, there are no studies evaluating molecular mechanisms of acid-induced bronchoconstriction. As discussed in Chapter 2, the autonomic nervous system plays a role in inducing neurogenic inflammation. This chapter will review data supporting a vagal reflex mechanism and data supporting a microaspiration model. Next, pulmonary mechanisms predisposing asthmatics to develop gastroesophageal reflux disease (GERD) are discussed including the role of the crural diaphragm in lower esophageal sphincter (LES) pressure generation, heightened thoraco-abdominal pressure differential predisposing to reflux development, and the effects of asthma medications on GERD. Finally, data examining predictors of asthma response from clinical trials 139

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will be reviewed, since these predictors provide insight into the underlying mechanisms of acid-induced bronchoconstriction. I.

Pathophysiology of Esophageal Acid-Induced Bronchoconstriction

There are three mechanisms in which GERD induces or exacerbates airflow obstruction in asthmatics, including first, a vagally mediated reflex where acid in the esophagus stimulates acid-sensitive receptors resulting in bronchoconstriction. Second, esophageal acid causes heightened bronchial reactivity, so that when an asthmatic is exposed to a trigger, there is a heightened bronchoconstrictive response. Third, microaspiration of gastric contents into the upper airway causes bronchoconstriction. These three mechanisms may interact and further augment airway responses. The vagus nerve is involved in all three mechanisms, including microaspiration. A.

Vagal Reflex Mechanism

The tracheobronchial tree and the esophagus share embryonic foregut origins and share autonomic innervation through the vagus nerve. Airway reflexes may be protective in order to avoid exposure to noxious agents by causing apnea, laryngeal narrowing, and bronchoconstriction, or defensive, aiming to remove noxious agents by sneezing or coughing (2). Stimulation of the upper aerodigestive tract leads to clinically significant respiratory responses (3). Osler was the first to propose that a vagally mediated reflex could exacerbate asthma (1). Vagal innervation of the esophagus includes both sensory and motor fibers. Sensory nerves in the esophagus respond to irritation and esophageal distention. Sensory information from the esophagus is conveyed through the vagus nerve to the nucleus of the solitary tract in the dorsomedial medulla. Interneurons then project from the nucleus of the solitary tract to motor neuron pools in the ventrolateral medulla just dorsal to the inferior olives in the region of the nucleus ambiguus. Motor efferents in the vagus nerve then travel to nerve endings in the tracheobronchial tree, resulting in bronchoconstriction (Fig. 1) (3). Reflux-induced bronchoconstriction was extensively investigated by Mansfield et al. (4). Using a dog model, they produced esophagitis by instilling hydrochloric acid (HCI) into the esophagus for a week (4). On testing day, anesthetized dogs sequentially had 100 ml of normal saline infused into their esophagii over 15 minutes, followed by an infusion of 0.1 N HCl, followed by lower esophageal distention using a 60-ml air-filled balloon. Total respiratory resistance and functional residual capacity (FRC) were measured at the conclusion of each procedure. In another group of experimental animals, bilateral vagotomy was performed before the esophageal manipulations (4). Esophageal acid caused a

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Figure 1 Central neural control of the esophagus and tracheobronchial tree through the vagus nerve. Sensory information from the esophagus is conveyed by the vagus nerve to the nucleus of the solitary tract (NTS) in the dorsomedial medulla. Interneurons project to the motor neuron pools in the ventrolateral medulla, after which motor efferents located in the vagus nerve project to the tracheobronchial tree. (Modified from Ref. 3.)

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significant fall in respiratory conductance, the reciprocal of total respiratory resistance. Esophageal distention also caused a similar fall in respiratory conductance. In the dogs who had bilateral vagotomy, the previously described fall in respiratory conductance did not occur, thus showing that the vagus nerve was involved in esophageal acid–induced bronchoconstriction. Esophagitis was found in all dogs. These findings support that esophageal acid or balloon distention of the distal esophagus in dogs with esophagitis causes bronchoconstriction (4). There are also human studies that support a vagally mediated reflex. Mansfield and Stein examined 15 asthmatics with GERD and monitored spirometry and total respiratory resistance at baseline, after 15 minutes of a normal saline esophageal infusion, and after an esophageal acid infusion of 0.1 N HCl for 30 minutes or until symptoms of esophagitis occurred (pyrosis) (5). Normal saline infusions caused no change in pulmonary function. When symptoms of esophagitis appeared with esophageal acid, there was an increase in total respiratory resistance and a decrease in airflow at 25% of vital capacity. Pulmonary function returned to baseline values after symptom relief with antacids. Since testing was performed in the upright position, the authors concluded that microaspiration was unlikely and that a reflex mechanism was responsible for the bronchoconstriction (5). The same group of investigators performed a double-blind esophageal acid infusion study in four subject groups: asthmatics with GERD, asthmatics without GERD, subjects with GERD, and normal control subjects (6). Esophageal acid infusion resulted in no change in pulmonary function in the asthmatics without GERD, with GERD, and the normal control groups. The asthmatics with a positive Bernstein test group had a 10% increase in total respiratory resistance when reflux symptoms occurred, which returned to baseline when reflux symptoms abated with antacids ( p ⬍ 0.01). The changes in total respiratory resistance were even more pronounced (72% over baseline) in asthmatics with GERD who associated asthma attacks with reflux symptoms ( p ⬍ 0.0001) (6). They concluded that a positive symptom response in an acid-sensitive esophagus of an asthma patient was required and that the rapid fall in total respiratory resistance after antacid treatment makes it likely that a reflex mechanism was involved (6). Other investigators, however, have found that the presence of reflux symptoms was not necessary to evoke airway responses with esophageal acid. Ducolone´ et al. monitored pulmonary function in 13 asthmatics with GERD and 7 asthmatics without GERD during esophageal acid infusions (7). There was a significant change in maximal expiratory flow at 50% and 25% of vital capacity after esophageal acid infusion in both the asthmatics with and the asthmatics without GERD without a significant change in FEV1 (7) Pulmonary function changes were not observed in patients with chronic bronchitis with or without GERD or in normal controls (7). To further examine the role of the vagus nerve in acid-induced broncho-

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constriction, investigators used atropine to block the parasympathetic reflex responses. Andersen et al. performed esophageal acid infusions in three groups: patients with esophagitis without asthma, patients with asthma without esophagitis, and asthmatics with esophagitis (8). Pulmonary function tests, including total lung capacity, airway resistance, residual volume, and peak expiratory flow rates were measured after esophageal infusions of 50 ml of normal saline and 50 ml of 0.1 N HCl. Esophageal infusions were also performed after an intravenous injection of atropine (0.01 mg/kg of body weight). There was a significant decrease in peak expiratory flow rate and an increase in airway resistance after HCl infusion seen only in the asthmatics with esophagitis. Six patients with asthma and esophagitis also received atropine pretreatment, and esophageal acid failed to produce changes in peak expiratory flow rate or airway resistance (8). They concluded that there is modest bronchoconstriction with esophageal acid in asthmatics with endoscopy-proven esophagitis. This response was inhibited with intravenous atropine, indicating vagal mediation (8). To further study acid-induced esophagobronchial-cardiac reflexes in humans, Wright et al. examined 136 unselected individuals with esophageal infusions of water, normal saline, and 0.1 N HCl (9). Highly significant reductions in airway flow measured by FEV1 (⬍0.0001) and oxygen saturation (⬍0.0001) were noted with esophageal acid. A positive Bernstein test was not necessary for these airway responses. Also, the previously noted decrements in airflow and oxygen saturation with esophageal acid infusion were absent in atropinepretreated (0.6 mg intramuscular) patients (9). These data indicate that the cholinergic reflex is universal, present not only in subjects with bronchospasm, but also in subjects without pulmonary symptoms. Also, an acid-sensitive esophagus (as defined by a positive Bernstein test) was not required to evoke the bronchoconstriction response (9). To further evaluate the pulmonary effects of esophageal acid, Kjellen et al. studied three study groups—15 patients with asthma and GERD, 5 patients with asthma and a negative Bernstein test, and 5 patients without asthma with GERD (10). Pulmonary function tests including vital capacity, closing volume, and slope of alveolar plateau were measured during esophageal acid infusion. There was a decrease in vital capacity of 0.2 liters and an increase in alveolar plateau of 0.9% in asthmatics with GERD, but not in the two other groups. All patients in the group with asthma and GERD had a positive Bernstein test, suggesting that an inflammatory reaction in the esophageal mucosa was necessary to elicit airflow obstruction with esophageal acid (10). Many asthmatics with GERD have nocturnal bronchospasm. Davis et al. studied respiratory responses with esophageal acid infusion in eight asthmatic children during sleep (11). On the basis of the Bernstein test, two groups were identified: those with and those without heartburn during the Bernstein test. Esophageal saline and acid infusions were administered at midnight and at 4:00

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a.m. Only asthmatics with a positive Bernstein test had a decrease in respiratory time fraction (40% decrease) and an increase in mean respiratory flow with esophageal acid. They concluded that there is an active reflex mechanism initiated from an inflamed esophagus causing bronchial smooth muscle contraction (11). Despite many studies showing evidence of acid-triggered bronchoconstriction, there are also studies that fail to show alterations in pulmonary function. Ekstro¨m et al. studied eight moderate to severe asthmatics with GERD, with four patients having reflux-associated respiratory symptoms (12). Subjects underwent histamine-inhalation testing to measure airway hyperresponsiveness: 2–3 hours later, esophageal acid infusions were performed with FEV1 measurements. They found that patients with reflux-associated respiratory symptoms had greater histamine reactivity than those without. A more negative change in FEV1 with esophageal acid was seen in patients with a positive Bernstein test (12). However, clinically significant bronchospasm and significant changes in FEV1 were not seen (12). Furthermore, Wesseling et al. studied 12 asthmatics with GERD and monitored spirometry and respiratory impedance after esophageal acid infusions and found no statistically significant difference in peak expiratory flow rate or impedance of the respiratory system with esophageal acid (13). They concluded that there was no evidence for a direct causal relationship between esophageal acid and increased bronchomotor tone (13). Since autonomic regulation is altered during sleep and airway responses may be augmented during sleep, Tan et al. monitored spontaneous esophageal acid events and performed esophageal acid infusions in 15 sleeping asthmatics (14). Respiratory parameters measured included airflow, tidal volume, and pulmonary resistance. Subjects were divided into those with a positive Bernstein test and those without. Lower airway resistance did not change on the night that the subject was exposed to esophageal acid. The presence of esophagitis, as defined by a positive Bernstein test, did not influence the pulmonary response to esophageal acid. Although meticulously executed, one potential problem with the study design is that the investigators combined data from spontaneous acid events and events during esophageal acid infusions. Their study population combined asthmatics with GERD and asthmatics without GERD (14). Previous studies have shown that a bronchoconstrictive effect is only present in asthmatics with GERD. There are many factors that could explain conflicting data. Studies show that esophageal acid may produce a modest bronchoconstrictive response, which may not be present in all subjects tested. In selected asthmatics, sensitive measurements of bronchoconstriction, including peak expiratory flow rate and airway resistance, were found. The magnitude of the change in these parameters was in the range of 10–20% with esophageal acid (15). Esophageal acid resulted in these changes more commonly in subjects with positive Bernstein tests or evidence of esophagitis than in subjects without evidence of GERD. Another problem with

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most of the studies is that the population size was small, especially in the control groups. Also, study group definitions and entrance criteria were poorly defined in some of the studies. No study reviewed thus far investigated the possibility of microaspiration of acid into the larynx or trachea. In order to further investigate the role of a vagally mediated reflex causing bronchoconstriction, our laboratory performed a series of studies, which included strictly defined patient populations. In the first study, 47 nonsmoking adult subjects were divided into four groups. The first group included 20 asthmatics with GERD (with asthma being defined by American Thoracic Society criteria) and evidence of airway hyperresponsiveness. GERD was defined by reflux symptoms including heartburn and/or regurgitation and abnormal esophageal acid contact times on 24-hour esophageal pH test (16). The second group included seven asthmatics without GERD. The third group included 10 patients with GERD, without pulmonary symptoms, and the fourth group included 10 normal controls who had normal esophageal pH tests, no pulmonary symptoms, and normal pulmonary function studies. To evaluate for microaspiration, dual esophageal pH monitoring was performed during esophageal infusions. The proximal esophageal pH probe measured pH just below the upper esophageal sphincter (UES), assuming that patients with proximal esophageal reflux have increased potential for microaspiration. Patients presented after an overnight fast and the dual esophageal pH probe was placed with pH electrodes 5 cm above a manometrically defined LES and just below the UES. Esophageal infusions of normal saline, 0.1 N HCl, and normal saline were performed in an order blinded to the patient at the rate of 7 ml per minute for 15 minutes (16). During the esophageal infusions, the patients sat upright in a chair and spontaneously reported pulmonary and reflux symptoms. Pulmonary function studies including spirometry and airway resistance were performed after the placement of the esophageal pH probe, after the insertion of the 8 French feeding tube, and after each esophageal infusion. Peak expiratory flow rate decreased with esophageal acid infusion in all four groups including normal controls ( p ⬍ 0.01) (Fig. 2). Furthermore, esophageal acid clearance improved peak expiratory flow rate in all groups except in the asthma with GERD group, which had a further decrease in peak expiratory flow rate. The bronchoconstrictor response was not dependent on a positive Bernstein test or evidence of proximal reflux, a prerequisite for microaspiration. Another interesting finding is that asthmatics with GERD also had an increase in specific airway resistance with esophageal acid, which continued to increase despite acid clearance. These results agree with Wright et al.’s data, which showed a decrease in airflow independent of whether the subject had pulmonary disease (9). Since microaspiration was not required for bronchoconstriction, a vagally mediated esophago-pulmonary reflex is present in all individuals. This reflex may be a protective mechanism for the lung, in that bronchoconstriction would decrease the lung’s exposure to caustic

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Figure 2 Peak expiratory flow rate data expressed as percent predicted during esophageal infusions of normal saline solution (NS) and acid. (From Ref. 16.)

agents. Another interesting finding is that asthmatics with GERD had no improvement in peak expiratory flow rate despite esophageal acid clearance, as documented by normalization of esophageal pH at the distal esophagus during the second saline infusion (16). The other study groups had complete recovery of peak expiratory flow rate with esophageal acid clearance. Asthmatics with GERD may have an exaggerated vagal reflex, which represents an aberration in parasympathetic tone. Another possible mechanism is that esophageal acid triggered, through a reflex, airway inflammation resulting in continued bronchoconstriction (16) (see Chap. 2). Subsequently, we infused esophageal acid with subjects in the supine position to examine if microaspiration was a factor (17). Thirty nonsmoking adults were divided into two groups: 20 asthmatics with GERD and 10 subjects with GERD. Patients underwent dual probe esophageal pH monitoring during esophageal infusions of normal saline, 0.1 N HCl, and normal saline, each lasting 18 minutes. Since the previous study showed a decrease in peak expiratory flow rate

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and an increase in respiratory resistance despite esophageal acid clearance in asthmatics with GERD, two 20-minute recovery periods were added to follow airway responses. The subjects remained in a supine position throughout the study. Spirometry and specific airway resistance were measured at baseline, after each esophageal infusion, and with each recovery period. Proximal esophageal acid exposure, a prerequisite for microaspiration, was assessed by the proximal esophageal pH probe. As in our previous study, peak expiratory flow rate decreased with esophageal acid in the asthma with GERD group and did not recover immediately despite esophageal acid clearance (17). The decrease in peak expiratory flow rate was not associated with the presence of proximal esophageal acid exposure. Specific airway resistance also increased in the asthma with GERD group with esophageal acid and continued to increase despite acid clearance, especially during the second recovery phase ( p ⬍ 0.009). The presence of proximal esophageal acid exposure was not associated with deterioration in specific airway resistance. These data show that esophageal acid infusion, given in the supine position, caused a decrease in peak expiratory flow rate and an increase in specific airway resistance, which did not improve despite esophageal acid clearance. These responses were not dependent on proximal esophageal acid exposure (17). Interestingly, specific airway resistance continued to worsen during the recovery phase in the asthma with GERD group, which may represent a prolonged bronchoconstrictor effect. These data suggested that a vagally mediated reflex was important and that microaspiration is not necessary for esophageal acid-induced bronchoconstriction. Also, in this study a positive Bernstein test was not required for the bronchoconstrictor response (17). Additionally, vagolytic doses of intravenous atropine partially ablated the bronchoconstrictor response in our model, further implicating a vagally mediated reflex (18). To further evaluate the role of the autonomic nervous system in esophageal acid–induced bronchoconstriction, we performed autonomic function testing in 15 asthmatics with GERD, hypothesizing that asthmatics with GERD have exaggerated vagal responsiveness (19). Autonomic function testing included a passive tilt (a 3-minute 80° upward tilt on a motorized table with a comfortable foot rest, followed by 3 minutes of continous monitoring on the return of the horizontal position), a Valsalva maneuver (a sustained forced expiration through a mouthpiece connected to an aneroid manometer set at (30 mmHg lasting 15 seconds, followed by deep inspiration), heart rate variation with quiet and deep breathing (six breaths per minute), hand grip (maximum force for 15 seconds), and an echostress test (cortical arousal was induced by listening on earphones to an outof-phase reproduction of a recording while reading aloud the same paragraph). Simultaneous heart rate and blood pressure readings were collected at set intervals throughout the testing period. The autonomic function test results of the asthmatics with GERD were compared to the responses of 23 age-matched nor-

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mal control subjects. Results of the autonomic function tests were classified as normal, hypervagal, hyperadrenergic, or mixed (a combination of hypervagal and hyperadrenergic responses). The overall response score was determined by the results of the tilt, Valsalva maneuver, and deep breathing maneuvers. Hypervagal responses on the tilt test and Valsalva maneuver are illustrated in Figure 3. Table 1 displays the autonomic function test results in the asthmatics with GERD. In the tilt test, 60% of asthmatics with GERD had a hypervagal response, 31% had a hypervagal response during the Valsalva maneuver, and 73% of asthmatics with GERD had a hypervagal response during the deep breathing maneuver. Interestingly, each asthmatic with GERD had at least one autonomic function test display a hypervagal response. The overall response score showed that no individual had a normal or hyperadrenergic response score. Fifty-three percent of asthmatics with GERD had a hypervagal response score, and 47% had a mixed response score (19). These data suggest that asthmatics with GERD have heightened vagal responsiveness, which may be partially responsible for the airway responses to esophageal acid. In conclusion, there appears to be a vagally mediated reflex causing bronchoconstriction when acid is infused into the esophagus, especially in asthmatics with GERD (4–11,16,17). These airway responses may be modest; however, they are present. Esophageal acid–induced bronchoconstriction is present in normal controls in some studies (9,16,17). Also, investigators have shown that the presence of esophagitis augments the bronchoconstrictor response (4,5,6,8,10,11). It appears that microaspiration, as defined by the presence of proximal esophageal acid, is not required for esophageal acid–induced bronchoconstriction (16,17). It is noteworthy that multiple investigators have shown that vagolytic doses of atropine diminish airway responses (8,9,18). Asthmatics with GERD also have evidence of autonomic dysfunction, with many individuals having a hypervagal response (19). Two studies have shown a delayed bronchoconstrictor response after esophageal acid clearance (17,18). This may reflect augmentation of airway inflammation through neurogenic stimulation.

Figure 3 Hypervagal response. Comparison of percent change in heart rate compared with baseline (x axis) and blood pressure (BP) (individual readings at time points) response to tilt test and Valsalva maneuver in control subjects and one study patient showing a hypervagal response. Note the subnormal increase in heart rate during the 80° tilt and inappropriate bradycardia during the recumbent phase. During the Valsalva maneuver, the study subject showed a subnormal increase in heart rate during the release phase and an inappropriate bradycardia during the recovery phase as compared with control subjects. (From Ref. 19.)

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Table 1 Autonomic Function Test Results in 15 Asthmatics with GERD Responsea Test

Normal

Tilt Valsalvab Deep breathing Echo stress Hand grip Overall

0 2 4 12 2 0

(0%) (15%) (27%) (80%) (13%) (0%)

Hypervagal 9 4 11 0 13 8

(60%) (31%) (73%) (0%) (87%) (53%)

Hyperadrenergic 1 2 0 3 0 0

(7%) (15%) (0%) (20%) (0%) (0%)

Mixed 5 5 0 0 0 7

(33%) (39%) (0%) (0%) (0%) (47%)

a

Expressed as number of individuals with each response (percentage of group). 13 of 15 patients were able to hold pressure for 15 seconds. Source: Ref. 19. b

B.

Heightened Bronchial Reactivity

Esophageal reflux may also cause neural enhancement of bronchial reactivity. Although the experimental observations discussed in the previous section suggest that, while individual exceptions occur, esophageal acid triggers bronchoconstriction, others have shown a poor temporal correlation between reflux episodes during esophageal pH monitoring and the onset of respiratory symptoms. Sontag et al., using esophageal pH monitoring and respiratory symptom correlation in 48 asthmatics, found that 54% of wheezing episodes had no relationship to reflux episodes (20). It is possible that there is an interactive mechanism between acid in the esophagus and other stimuli that produce bronchoconstriction and that these interactive events are larger than the primary effect of isolated acid infusion on bronchomotor tone. Esophageal reflux may worsen airflow by increasing bronchomotor responsiveness to other stimuli. To examine this possibility, Herve et al. examined the effect of esophageal acid infusion on the bronchomotor response to two nonspecific stimuli used in bronchial provocation tests: voluntary isocapnic hyperventilation of dry air and methacholine inhalation challenge (21). Twelve adult asthmatics participated irrespective of the presence of GERD and all underwent 12 hours of overnight esophageal pH monitoring. To examine airway hyperresponsiveness, voluntary isocapnic hyperventilation of dry air and methacholine challenge tests were performed after esophageal infusion of isotonic saline and, on another day, esophageal acid. Seven control subjects also participated. Of the 12 asthmatics, seven had GERD defined by esophageal pH monitoring. Esophageal acid did not affect maximum expiratory flows or voluntary isocapnic hyperventilation response of dry air in normal subjects. However, in asthmatics, esophageal acid markedly potentiated the bronchoconstriction induced by voluntary isocapnic hyperventilation com-

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pared to normal saline infusion ( p ⬍ 0.001). Similarly, during methacholine challenge, the dose of methacholine that produced a 20% fall in FEV1 (PD20) significantly decreased with esophageal acid infusion compared with saline ( p ⬍ 0.01), as shown in Figure 4. Comparing the bronchial responses of asthmatics with GERD versus asthmatics without GERD, the asthmatics with GERD had a greater bronchoconstrictive response compared to asthmatics without GERD ( p ⬍ 0.01). Three asthmatics with GERD received atropine pretreatment (2 mg intramuscular), which caused an increase in the baseline maximum expiratory flow at 50% of FVC, but prevented the decrease in maximum expiratory flow at 50% of FVC during esophageal acid infusion (21). This study showed that esophageal acid, without additional bronchial stimulation, caused slight bronchoconstriction in asthmatics with GERD, but not in normal controls or in asthmatics without GERD. Even more impressive was the fact that esophageal acid altered the underlying bronchial reactivity to other stimuli, even in asthmatics without GERD, in whom acid perfusion alone produced

Figure 4 Provocative doses of methacholine causing a 20% decrease in FEV1 (PD20) in five asthmatics during esophageal NaCl and HCl infusion (open and closed symbols for, respectively, patients without and with GERD). The change in PD20 is shown for each subject. (From Ref. 21.)

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no bronchoconstriction. Vagal pathways are also important since the bronchial response to esophageal acid was abolished with atropine pretreatment (21). This study supports the hypothesis that esophageal acid stimulates esophageal acid– sensitive receptors and probably interacts with cholinergic airway tone at a central nervous system level through a vagally mediated reflex. To further support the bronchial hyperresponsiveness model, it would be optimal to show that antireflux treatment decreases airway hyperresponsiveness in provocation tests. To date, there are no studies that show that antireflux therapy decreases bronchial responsiveness. In a study performed by Teichtahl et al. omeprazole 40 mg a day for 4 weeks did not change histamine bronchial responsiveness (22). Since 17 of 20 subjects had esophagitis documented by upper endoscopy, 4 weeks of antireflux therapy might not have been adequate to heal esophagitis. The subjects did not have repeat endoscopy to document if healing of esophagitis occurred. Also, once-daily dosing of omeprazole does not suppress esophageal acid production throughout the 24-hour period, so that the therapeutic trial may not have been adequate to document a decrease in bronchial hyperreactivity (23). The data do suggest that esophageal acid augments airway hyperreactivity in asthmatics. Asthma is a heterogeneous disease exacerbated by multiple triggers, so that when an asthmatic with GERD is exposed to an allergic trigger, such as cat dander, or a nonallergic trigger, such as cigarette smoke, they may have an exaggerated bronchoconstrictive response. C.

Microaspiration

Microaspiration of esophageal contents into the upper airway is the third mechanism of esophageal acid–induced bronchoconstriction. Microaspiration of refluxed material needs to be distinguished from macroaspiration or ‘‘flooding’’ of the tracheobronchial tree, which leads to clinical entities such as pneumonia, pneumonitis, lung abscess, and bronchiectasis (24,25). In the microaspiration model, gastric material refluxes to the proximal esophagus, then into the hypopharynx and possibly into the larynx and trachea. Microaspiration directly irritates the airways and causes reflex bronchoconstriction. It is well established that mechanical stimulation of the upper airway or installation of saline into the trachea causes an increase in resistance (26,27). To examine the effect of microaspiration on airway responses, Tuchman et al. developed an animal model comparing airway responses of esophageal acid (reflex mechanism) versus tracheal acid (microaspiration mechanism) in cats (28). In a series of experiments, they showed that microaspiration of acid into the trachea causes more airway responses than esophageal acid reflux. Their experimental preparation used anesthetized adult cats breathing spontaneously through an airway cannula in the trachea. Pulmonary mechanics including pulmo-

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nary airflow, total lung resistance, and dynamic compliance were measured. A pleural catheter measured pleural pressure. Esophageal manometry located the LES and the UES, and an esophageal pH probe was placed in the upper esophagus to monitor for proximal esophageal reflux. Measurements of airway mechanics were determined before, during, and after either 0.9% saline or 0.2 N HCl infusion into the trachea or esophagus in 13 animals. To determine the mechanism of the observed response to tracheal acid, bilateral cervical vagotomy was done. To determine if the presence of esophagitis augmented airway responses after esophageal acid, 0.2 N HCl was infused into the midesophagus over a 30-minute period for 2–3 days before the study, with esophagitis documented by biopsies (28). Figure 5 shows the lung mechanics after esophageal acid infusion of 10 ml of 0.2 N HCl over a 20-second period. In most animals, no gross change in respiratory pattern was evident from viewing the raw tracings (28). Further analysis shows that there was a 1.42-fold increase in total lung resistance compared to baseline after esophageal acid ( p ⬍ 0.05) (28) A significant increase in total lung resistance occurred in only 60% of the animals tested. The presence of esophagitis did not enhance the airway response to esophageal acid. In contrast, tracheal acidification with 0.05 ml of 0.2 N HCl resulted in significant alterations in lung mechanics, which was observed in all animals. Figure 6 shows that with tracheal acidification, there is interruption of tracheal airflow with large pleural pressure changes and a decrease in tidal volume. There

Figure 5 Lung mechanics after esophageal acid infusion. Baseline measurements are to the left of the dotted line. Ten milliliters of 0.2 N HCl into the esophagus caused minimal increase in pleural pressure and tracheal airflow. (From Ref. 28.)

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Figure 6 Lung mechanics after intratracheal acid infusion. Baseline measurements are to the left of the dotted line. Immediately after tracheal acidification of 0.05 ml of 0.2 N HCl, there is an increase in intrapleural pressure and a decrease in tidal volume and airflow. (From Ref. 28.)

was a 4.65-fold increase in total lung resistance compared to baseline ( p ⬍ 0.005), as shown in Figure 7. Also, the bronchial response to tracheal acidification was concentration dependent, with 0.001 N HCI causing no significant change in resistance versus a 3-fold increase in resistance with 0.1 N HCI and a 4.65fold increase with 0.2 N HCI (28). The vagus nerve also plays a role in the microaspiration model. The increase in total lung resistance associated with tracheal acidification was abolished with bilateral cervical vagotomy, as shown in Figure 7 (28). No alteration in breathing pattern was noted after tracheal acidification in vagotomized animals (28). Scintigraphy of the chest in cats after tracheal instillation of 0.05 ml of technicium labeled 99m-sulfur colloid showed that the instilled liquid remained in the trachea and did not spread into the major bronchi or lung parenchyma (28). It is much more difficult to monitor airway responses in humans with tracheal acidification or to monitor for microaspiration. Three methods have been used to demonstrate microaspiration of gastric contents into the lungs of humans: (a) inspection of sputum or bronchoalveolar lavage for lipid-laden alveolar macrophages, (b) radioactive labels, and (c) pH monitoring in the upper esophagus or trachea.

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Figure 7 Total lung resistance after intratracheal infusion of 0.05 ml of 0.9% NaCl, 0.2 N HCl prevagotomy, and 0.2 N HCl postvagotomy. Intratracheal acid produced a highly significant increase in the resistance ratio compared to saline. The effect of intratracheal acid was abolished by bilateral cervical vagotomy. (From Ref. 28.)

Lipid-laden alveolar macrophages were evaluated in adults as a marker of aspiration by examining lower respiratory secretions obtained by bronchoalveolar lavage and stained for Oil-Red-O (29). Corwin and Irwin found that low numbers of intracellular Oil-Red-O–stained alveolar macrophages may be helpful in excluding aspiration as a cause of lung disease (29). Normal controls also had lipidladen alveolar macrophages. Unfortunately, the finding of lipid-laden macrophages in children and adults has a very low specificity, making the test clinically impractical and difficult to correlate with bronchoconstriction (29,30). Another method used to assess for microaspiration is scintigraphic monitoring using technetium 99 isotope-sulfur colloid. A radiolabeled meal or liquid is ingested and the subjects are later scanned. Increased uptake over the lungs is evidence for aspiration (31–34). In most studies, subjects went to sleep after eating (31–34). While many asthmatics had positive scans, only approximately 25–31% of those tested showed evidence of aspiration (30–35). One study showed evidence of aspiration in 38% of control subjects (35). Since the subjects were given the test meal prior to lying in the supine position and sleeping, they were predisposed to develop reflux and aspiration. Esophageal pH was monitored concurrently in five subjects with no respiratory symptoms. Two of the five subjects had abnormal scintiscans and prolonged episodes of esophageal acid (34). Despite reports of its usefulness in documenting aspiration, it has many limita-

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tions. The small amount of microaspiration required to cause bronchospasm may escape detection with currently employed scanning methods. Aspiration may be undetected if mucociliary action of the bronchial epithelium clears the technetium. Aspiration may occur only intermittantly so that multiple scans are required to increase the test’s sensitivity. There is also high background radioactivity in the abdomen, which may make the test difficult to interpret. In conclusion, scintigraphic monitoring is not very useful in assessing mechanisms of GERD-associated bronchoconstriction. Monitoring pH in the proximal esophagus and upper airway allows correlation of acid events with respiratory symptoms and alterations in airway function. Most investigators used dual pH probes with the distal sensor in the esophagus 5 cm above the LES and the proximal probe near the UES in the upper esophagus. Pharyngeal probes above the UES have been unreliable because of drying artifact of the probe (34). To evaluate the frequency of proximal esophageal reflux, a marker for microaspiration, Gastal et al. evaluated asthmatics referred to an esophageal laboratory for the possibility of GERD (37). Although, 44% of asthmatics had abnormal esophageal acid contact times in the distal esophagus, abnormal amounts of esophageal acid in the proximal probe was found in only 24% of asthmatics. They concluded that microaspiration was not as important as reflux-mediated bronchospasm (37). They did not monitor airway responses during the evaluation period. Varkey et al. evaluated 19 consecutive asthmatics and 7 normal controls with dual esophageal pH monitoring (5 cm above the LES and 5 cm below the UES) and a probe in the pharynx 2 cm above the UES (38). Patients with moderate or severe asthma had 31% of reflux episodes associated with a full in pH at the proximal esophagus and 5% of episodes associated with acid in the pharyngeal probe, documenting that microaspiration does exist and is more prevalent in asthmatics than in normal controls (38). The investigators did not monitor airflow with reflux events. The best human data that show the significance of microaspiration in acidinduced bronchoconstriction were reported by Donnelly et al., with follow-up data reported by Jack et al. from Liverpool (39,40). They monitored simultaneous tracheal and esophageal pH in asthmatics and measured airway responses with peak expiratory flow rates. The tracheal pH probe was placed by introducing the probe through a 13 or 14 French cannula, which was placed through the skin and the cricothyroid membrane under anesthesia. The tracheal pH probe was positioned under bronchoscopic guidance 2 cm above the carina. The cannula was removed and the probe taped to the patients’ neck. The esophageal pH probe was placed 5 cm above the LES. Four patients with GERD underwent simultaneous pH monitoring and recorded peak expiratory flow rates hourly during 24 hours. Thirty-seven episodes of gastroesophageal reflux at the esophageal probe

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were recorded lasting more than 5 minutes. Of these, five esophageal events were closely followed by a fall in tracheal pH from a mean of 7.1 to 4.1. Figure 8 displays one such episode. When esophageal acid events occurred without a fall in tracheal pH, peak expiratory flow rates dropped an average of 8 liters per minute. When esophageal acid events were followed by a fall in tracheal pH, peak expiratory flow rates decreased 84 liters per minute (40). Unlike esophageal acid events without evidence of microaspiration, tracheal microaspiration of acid caused significant acute changes in lung function in asthmatics with GERD. This study shows that microaspiration, if present, significantly augments airway responses and plays a key role in the pathophysiology of acid-associated bronchoconstriction. D. Conclusions on the Pathophysiology of Esophageal Acid–Induced Bronchoconstriction

Data suggest that all three mechanisms play a role in esophageal acid–induced bronchoconstriction. Animal and human studies show that there is evidence of bronchoconstriction with esophageal acid in the distal esophagus (4,11,16,17).

Figure 8 Segment from tracheal pH (broken line) and esophageal pH (solid line) showing an esophageal acid event followed by a prolonged drop in tracheal pH. The subject was awake and wheezing during this time and required an inhaled bronchodilator. (From Ref. 39.)

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The bronchoconstriction elicited is somewhat modest, but present. There is debate as to whether this vagally mediated reflex is present in all individuals or primarily in asthmatics with GERD. Studies performed by Wright et al. and a series of studies performed by our laboratory show that even normal controls have evidence of bronchoconstriction with esophageal acid (9,16,17). The magnitude of airway change is a decrement of approximately 10 liters per minute in peak expiratory flow rate (16,17). Numerous studies have shown that airway resistance increases with esophageal acid (5–8,16,17). Most studies did not rule out the possibility of microaspiration as the cause for the airway responses. However, our laboratory, performing dual probe esophageal pH monitoring, found that proximal esophageal acid, a prerequisite of microaspiration, was not necessary to elicit bronchoconstriction (16,17). Some investigators, however, did not find evidence of bronchoconstriction with esophageal acid (12–14). Tan et al.’s study was well done, but it failed to reveal evidence of acid-induced bronchoconstriction with spontaneous esophageal acid or esophageal acid infusion (14). Further proof that a vagally mediated reflex is active was shown by Mansfield et al. in a dog model where bilateral vagotomy obliterated the airway responses to esophageal acid (4). Multiple investigators used atropine either intravenously or intramuscularly and showed that airway responses with esophageal acid were ablated or at least partially decreased with esophageal acid (8,9,18). There is also conflict in the literature as to whether distal esophagitis is required to elicit airway responses. The requirement of distal esophagitis could paritally explain Tan et al.’s and Wesseling et al.’s failure to elicit airway responses with esophageal acid (13,14). Other investigators have shown, however, that distal esophagitis, as defined by a positive Bernstein test, was not required to elicit airway responses (9,16,17). Further investigation needs to be performed to clarify this. In at least two studies, there is evidence of a prolonged increase in airway resistance, despite esophageal acid clearance (16,17). This may reflect neurogenically mediated inflammation and mediator release. Currently, there are no studies evaluating molecular mechanisms of airway inflammation in esophageal acid–induced bronchoconstriction. The second mechanism, heightened bronchial reactivity, is a subset of the vagally mediated reflex mechanism. Esophageal acid does cause an increase in airway bronchial reactivity as tested by methacholine challenge testing and voluntary isocapnic hyperventilation (21). Atropine also inhibits this heightened bronchial reactivity, so the vagus nerve also plays a role in this model (21). Animal and human studies show that microaspiration causes significant alterations in pulmonary mechanics (28,40). The magnitude of airway responses to acid placed directly into the trachea is fivefold over baseline versus 1.5-fold with esophageal acidification in an animal model (28). In human studies, tracheal acidification caused a tenfold worsening in airflow, with peak expiratory flow

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rate decreasing 85 liters per minute versus an 8 liter per minute decrease with distal esophageal acid. (40). Figure 9 shows that there is a vagally mediated response with distal esophageal acid causing bronchoconstriction through the vagus afferents projecting into the central nervous system, and the efferent limb mediating bronchoconstriction

Figure 9 Esophageal acid induced bronchoconstriction where distal esophageal acid stimulates the afferent sensory limb of the vagus nerve, resulting in reflex-induced bronchoconstriction. Microaspiration augments the bronchoconstrictive response.

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through cholinergic mechanisms. If microaspiration is present, there is augmentation of the bronchoconstrictive response. There is evidence that the vagus nerve plays a prominent role in all three mechanisms. Even in the microaspiration model, bilateral vagotomy ablated the response to tracheal acidification (28). In the tracheobronchial tree, there are C fiber endings, which could mediate bronchoconstriction, and slowly adapting stretch receptors, which could also cause bronchoconstriction (2). Figure 10 shows how all three mechanisms interact through the vagus nerve leading to airway inflammation. II. Factors That Could Promote GERD in Asthmatics The incidence and severity of GERD in asthmatics is higher than in the normal population. In a GERD questionnaire sent to 109 asthmatics and 135 subjects in two control groups, Field et al. noted that 77% of the asthmatics experienced heartburn, 55% had regurgitation, and 24% had dysphagia versus 54, 41, and 11%, respectively, of patients from a family practice population (41). Likewise, the prevalence of abnormal esophageal acid contact times is higher in asthmatics than in normal controls. Sontag et al. evaluated 104 consecutive asthmatics and 44 normal controls with esophageal manometry and pH monitoring and found abnormal amounts of acid reflux in 82% of asthmatics (42). In addition, asthmatics, compared to controls, had decreased LES pressures, more frequent reflux episodes, and higher esophageal acid contact times (42).

Figure 10 Esophageal acid–induced bronchoconstriction, showing the role of the vagus nerve, heightened bronchial reactivity, and microaspiration resulting in airway inflammation. (From Ref. 42a.)

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There are a number of physiologic parameters that may contribute to the development of GERD. Gastric factors include delayed gastric emptying and gastric distention placing greater stress on the antireflux barrier (43). The lower esophageal sphincter (LES) plays a key role in the antireflux barrier (44). Intrinsic muscles in the high-pressure zone of the distal esophagus and the crural diaphragm contribute to LES pressure generation (44). Transient LES relaxation and a low resting LES pressure predisposes to the development of reflux (44). Another factor that contributes to GERD is the length of the esophagus, which is in the abdominal cavity. DeMeester et al. noted that the amount of esophageal acid inversely correlated with the length of the esophagus below the diaphragm (45). A hiatal hernia may also impair esophageal acid emptying (44,46). Factors that predispose asthmatics to develop GERD include the possibility of autonomic dysfunction, since a substantial component of esophageal neurogenic tone in humans is from cholinergic innervation from the vagus nerve (44). Also, with bronchospasm there is an increase in the pressure gradient between the thorax (esophagus) and abdominal cavity (stomach) promoting reflux (47). Another factor is that asthmatics may have a higher prevalence of hiatal hernia than normal controls (48). Overinflation of the diaphragm may decrease the LES pressure because of the inability of the crural diaphragm to contribute to LES pressure generation. Also, bronchodilators, including theophylline and β2-adrenergic agonists, may promote reflux (Table 2). A. Autonomic Regulation

Lower esophageal sphincter tone, including relaxation of the sphincter, is mediated through the dorsal nucleus of the vagus nerve (44). Asthmatics have evidence of widespread cholinergic hyperresponsiveness. Asthmatics have increased eccrine sweat production after intradermal stimulation by methacholine (49). Also, asthmatics have increased pupillary cholinergic responsiveness compared to normal controls (50). Kallenback et al. showed evidence of enhanced parasympathetic neural drive to the sinoatrial node in asthmatics, as manifested by a greater

Table 2 Predisposing Factors in Asthmatics That Could Predispose to the Development of GERD 1. 2. 3. 4. 5.

Autonomic dysregulation Increased pressure differential between the thorax and the abdomen High incidence of hiatal hernia Crural diaphragm alterations Bronchodilators may decrease LES pressure and increase gastric acid secretion (theophylline and oral β2-adrenergic agonists)

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magnitude of respiratory sinus arrhythmia induced by deep breathing, than in normal controls (51). Our laboratory performed autonomic function tests on 15 asthmatics with GERD, and there was evidence of autonomic dysfunction (19). In 73 autonomic function tests performed, a normal response was found in 20 (27%), a hypervagal response in 37 (51%), a hyperadrenergic response in 6 (8%), and a mixed response in 10 (14%) (Table 1) (19). These data suggest that there may be heightened vagal responsiveness in asthmatics with GERD. Autonomic dysregulation could result in decreased LES pressure and transient relaxation of the LES, the principal mechanisms of reflux (44). Further research into autonomic regulation needs to be performed before further conclusions can be reached. B.

Pressure Differential Between the Thorax and the Abdomen

At the end of expiration, the pressure gradient between the stomach (abdominal cavity) and esophagus (thorax) is 4–6 mmHg. Therefore, a normal LES pressure of 10–35 mmHg at end-expiration is sufficient to counteract this pressure gradient (44). Contraction of inspiratory muscles causes more negative pleural pressures (esophageal), and contraction of abdominal muscles causes increases in gastric pressure, thus increasing the pressure gradient, favoring gastroesophageal reflux (44). With an acute asthma exacerbation, there are wide pressure swings with a much more negative intrathoracic pressure with inspiration and a more positive abdominal pressure, exaggerating the pressure gradient (47). Also, this effect is coupled with active expiratory efforts generated primarily by contraction of the abdominal muscles, resulting in higher gastric pressures. Coughing is also associated with contraction of the abdominal muscles increasing abdominal pressure and promoting GERD (52). Moote et al. showed that methacholine-induced airflow obstruction was associated with longer periods of reflux than during baseline studies (53). However, Ekstro¨m and Tibbling could not reproduce these data using histamineinduced bronchoconstriction in 10 asthmatics with GERD (54). Another clinical entity associated with large pleural (esophageal) pressure changes is obstructive sleep apnea. During an apneic event, there is upper airway collapse with upper airway obstruction with increased respiratory efforts (55). There is increased work of breathing shown by increased intercostal EMG activity and increased esophageal pressure. Kerr et al. noted that reflux events were prominent during apneic events (56). Nasal continuous positive airway pressure (CPAP) decreased the frequency of GERD (56). Although the exact mechanism is not known, CPAP raises thoracic (pleural) pressure and probably esophageal pressure. Also, treatment of obstructive sleep apnea with CPAP decreased the wide pleural pressure swings. Kerr et al. also showed that nasal CPAP decreased esophageal acid events in patients with GERD without obstructive sleep apnea (57).

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A small randomized double-blind crossover study was performed on five nocturnal asthmatics with GERD. Singh et al. observed daily asthma and gastric symptoms on and off ephedrine 15 mg for one week (58). Asthma treatment reduced asthma symptoms from six to one days per week, with a reduction of gastric symptoms from 4.8 to 1.6 days per week (58). Although definitive conclusions cannot be made, reflux may have improved because of the reduction in the abdominal-thoracic pressure gradient. C. Asthmatics Have a High Incidence of Hiatal Hernia

Although reflux occurs without the presence of a hiatal hernia, many GERD patients have a hiatal hernia, which can serve as a reservoir for gastric contents (59). Mittal et al. observed that transient relaxation of the LES is more likely to be followed by an episode of reflux if there is a hiatal hernia with retained acid than in the absence of a hiatal hernia (60). Asthmatics may have a higher incidence of hiatal hernia. Mays examined 28 asthmatics with severe asthma with upper gastrointestinal (UGI) series and compared them with a control group of 468 subjects that had a UGI series to establish the baseline incidence of hiatal hernia (48). Eighteen (64%) of the asthmatics had a hiatal hernia compared to 92 (19%) of normal control subjects ( p ⬍ 0.001) (48). In a more recent study, Sontag et al. performed endoscopy on 186 consecutive, unselected asthmatics (61). A hiatal hernia was present during endoscopy if gastric folds were seen extending at least 2 cm above the diaphragmatic hiatus during quiet respirations (61). Fifty-eight percent of asthmatics had a hiatal hernia (61). D. The Role of the Diaphragmatic Crura in LES Pressure Formation

The sphincter mechanisms at the boundary between the esophagus and stomach protect against acid reflux and consists of smooth muscle of the distal esophagus forming the LES and the skeletal muscle of the crural diaphragm (Fig. 11) (44). The crural part of the diaphragm originates embryologically from the esophageal mesentary, unlike the costal part of the diaphragm, which originates from the pleuroperitoneal membrane (62). The crural part of the diaphragm, especially the right crus, forms the esophageal hiatus (63). Multiple investigators have shown that transient relaxation of the LES and the crural diaphragm are responsible for GERD. There is relaxation of the LES associated with an inhibition of the diaphragmatic EMG associated with an increase in esophageal pressure leading to a reflux episode (64,65). Transient relaxation of the LES may last as long as 60 seconds (64,65). Transient relaxation of the LES is mediated through the brainstem, with the efferent pathway being the vagus nerve (44). Asthmatics may have alterations of their crural diaphragm. Hyperinflation associated with bronchospasm places the diaphragm at a functional disadvantage

Figure 11 Anatomy of the esophagogastric junction. The lower esophageal sphincter and the crural diaphragm constitute the intrinsic and extrinsic sphincters. The two sphincters are anatomically superimposed and are anchored to each other by the phrenoesophageal ligament. (From Ref. 44.)

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because of geometric flattening (66). Flattening and stretching of the diaphragmatic crura may occur with chronic hyperinflation and air trapping. E. Bronchodilator Medications May Alter GERD

There are data showing that bronchodilators may worsen GERD; however, there is debate about the clinical importance of this. Theophylline and oral β2-adrenergic agonists have significant effects on LES pressure. Theophylline Effects on GERD

Theophylline is a methylxanthine that alters gastric acid secretion and LES pressure. Foster et al. evaluated gastric acid secretion and gastrin release in nine patients with chronic obstructive pulmonary disease (67). Patients received intravenous aminophylline 6 mg/kg over a 20-minute period. Intravenous aminophylline caused a significant increase in gastric acid secretion from 0.66 to 2.19 mEq/ min ( p ⬍ 0.01) (67). Oral aminophylline (400 mg) also caused a significant increase in gastric acid secretion from 2.43 to 4.06 mEq/min ( p ⬍ 0.05) (67). The effect of theophylline on acid secretion was also shown by Johannesson et al. (68). Theophylline 5.0 mg/kg given intravenously by an infusion pump over 20 minutes resulted in serum theophylline levels of 10.0 mg/liter and an increase in gastric acid secretion and gastric volume compared to placebo in healthy male volunteers ( p ⬍ 0.01). There was no effect of theophylline on serum gastrin (68). Stein et al. monitored the effect of theophylline on LES pressure in four normal controls and six asthmatics with GERD (69). Intravenous theophylline 6.6 mg/ kg was given over 10 minutes (69). Theophylline levels were monitored at 30, 60, and 90 minutes after the start of the aminophylline infusion with all subjects maintaining therapeutic theophylline levels (10–20 mg/liter 60 minutes after the start of the infusion. Lower esophageal sphincter pressures were measured at baseline and at 60 minutes after the start of the aminophylline infusion. Figure 12 shows individual responses of the LES pressure in asthmatics with GERD given theophylline. All but one subject had a decrease in mean LES pressure ( p ⬍ 0.02) (69). Berquist et al. evaluated the effect of a single oral 10 mg/kg dose of theophylline versus placebo in 24 normal subjects and monitored LES pressure and esophageal pH while instilling 150 ml 0.1 N HCl into their stomachs (70). Four hours after theophylline dosing, there was a mean 25% decrease in LES pressure. Forty-seven percent of the theophylline-treated individuals complained of heartburn versus 11% of the placebo group. This shows that theophylline decreases LES pressure and increases the incidence of a positive acid reflux test and symptoms of heartburn compared with adults given placebo (70). Further studies evaluating the impact of theophylline on reflux in asthmatics with GERD were performed by Ekstro¨m et al. (71). They evaluated 25 adult

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Figure 12 Mean lower esophageal sphincter pressure (LESP) at baseline and at 60 minutes after the start of a 20-minute intravenous aminophylline infusion in four normal controls and six asthmatics with GERD symptoms. Intravenous aminophylline caused a significant drop in LESP. (From Ref. 69.)

asthmatics with moderate-to-severe asthma and a history of GERD in a singleblind placebo-controlled trial. Patients underwent two consecutive esophageal pH tests, one with and one without their ordinary dose of slow-release theophylline. Patients also recorded respiratory and GERD symptoms. Peak expiratory flow rate and FEV1 were recorded. Daytime reflux increased by 24% on theophylline. Symptoms of heartburn and regurgitation increased by 170%, while respiratory symptoms and pulmonary function studies improved on the day in which theophylline was given. The increase in GERD during theophylline treatment was more pronounced in patients with a therapeutic serum theophylline level (71).

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There are, however, conflicting results. Hubert et al. performed a doubleblind crossover study in 16 asthmatics, not selected for GERD, who were given a week of slow-release theophylline or placebo (72). Patients monitored peak expiratory flow rate three times daily, with spirometry weekly and theophylline levels at 2 and 7 hours after p.m. dosing. Esophageal pH testing was performed at the end of therapy with either theophylline or placebo. FEV1 and FVC improved during the theophylline period versus placebo. Similarly, there was no significant difference in the number of reflux episodes, total duration of reflux, number of reflux episodes lasting more than 5 minutes, or the percent of time the pH was less than 4 (72). They concluded that conventional treatment with slow-release theophylline did not significantly increase GERD. Two letters to the editor questioned their results (73,74). Mansfield questioned the statistical analysis performed (74). However, statistical analysis using Wilcoxon signedrank test failed to reveal a significant change in reflux parameters with placebo versus theophylline (74). Stein pointed out that the study population used by Hubert et al. were asthmatics who may not have had GERD (73). In conclusion, theophylline increases gastric acid secretion and decreases LES pressure. This makes asthmatics more prone to develop GERD. Investigators have found that higher levels of theophylline resulted in higher esophageal acid contact times. There are conflicting data in the literature. Most placebo-controlled trials were done on small patient populations. Some populations were not pure and included asthmatics with or without GERD. Since theophylline could worsen GERD, it should be used cautiously, especially at high doses. Effects of β2-Adrenergic Agonists on GERD

Foster et al. examined basal gastric acid secretion in nine patients with chronic obstructive pulmonary disease after using inhaled epinephrine hydrochloride, isoproterenol hydrochloride, and metaproterenol sulfate, finding that the agents did not cause significant changes in basal gastric acid output (67). They concluded that β2-adrenergic agonist therapy, in general, does not significantly alter gastric acid secretion (67). Interestingly, Christensen found that there was relaxation of the LES with β2-adrenergic agonists (75). However, adrenergic agents used in asthma did not significantly effect esophageal motility (75). DiMarino et al. found that oral or intravenous β2-adrenergic agonists decreased LES pressure (76). However, since most β2-adrenergic agonists are given by the inhaled route, these findings may not be clinically relevant in most patients (76). Other investigators have shown that inhaled β2-adrenergic agonists caused no significant change in GERD parameters or esophageal motility. Schindlbeck et al. examined the effect of albuterol 1.25 mg per nebulizer on 24-hour esophageal pH testing and esophageal manometry in 10 healthy volunteers in a doubleblind placebo-controlled trial (77). LES pressure, esophageal peristaltic ampli-

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tudes, and esophageal acid contact times were unchanged during placebo treatment versus nebulized albuterol (77). They concluded that inhaled albuterol does not significantly alter reflux parameters (77). Michoud et al. studied the effect of an oral β2-adrenergic agonist, salbutamol, on GERD in 10 healthy volunteers and 8 asthmatics (78). Patients were given salbutamol 4 mg or placebo with the order of administration randomized in a double-blinded fashion. There was no significant difference in LES pressure, peak esophageal contraction pressure, number or duration of reflux episodes between asthmatics and normal controls on placebo versus oral salbutamol (78). Although multiple studies have shown no significant alteration in GERD with inhaled β2-adrenergic agonists, Bittinger et al. studied seven patients with chronic obstructive pulmonary disease and noted higher total reflux times after inhalation of 400 mg of fenoterol (79). Although this was a small study, they concluded that obstructive pulmonary disease should be treated with the lowest possible doses of inhaled β2-adrenergic agonists (79). It appears that the β2-adrenergic agonists have less effect on esophageal function than theophylline. Ruzkowski et al. studied nine male patients with chronic obstructive pulmonary disease and GERD with nebulized albuterol 0.5 mg four times a day versus theophylline and monitored 24-hour esophageal pH testing and pulmonary function (80). Pulmonary function results were similar with the two treatments. Theophylline caused higher esophageal acid contact times than albuterol. Patients on albuterol also had fewer reflux episodes lasting longer than 5 minutes than while on theophylline (80). Inhaled β2-adrenergic agonists are important therapeutic agents for the treatment of asthma, especially during an acute exacerbation. Most studies show that inhaled β2-adrenergic agonists do not cause significant alterations in esophageal manonmetry, LES pressure, gastric acid secretion, or esophageal acid contact times. There is some controversy concerning whether inhaled β2-adrenergic agonists can predispose patients to develop GERD. Studies Evaluating Multiple Bronchodilators

Sontag et al. examined the frequency of esophagitis in 186 consecutive asthmatics on versus off bronchodilators (61). One hundred and forty asthmatics underwent endoscopy while taking their usually prescribed bronchodilators, including theophylline, terbutaline, inhalers, and prednisone, and 46 were studied without bronchodilators. Thirty-eight percent of asthmatics had esophagitis on bronchodilators versus 39% of asthmatics not on bronchodilators ( p ⫽ nonsignificant) (61). Although the study did not analyze the effects of individual medications, their results show that asthmatics on chronic bronchodilator therapy have the same prevalence of esophagitis compared to asthmatics not on bronchodilators (61). They concluded that bronchodilators did not adversely affect the esophageal mucosa (61).

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Sontag et al. also evaluated 104 consecutive asthmatics with esophageal manometry and 24-hour esophageal pH testing (42). Seventy-four asthmatics were studied while taking their usual bronchodilators, including theophylline, oral terbutaline, inhalants (adrenergic, anticholinergic, corticosteroid) and prednisone, while others were not on routine bronchodilators (42). There was no significant difference in LES pressure (13.0 ⫾ 1.0 on medications vs. 12.6 ⫾ 1.8 off medications), percent time where distal esophageal pH ⬍ 4 (10.8 ⫾ 1.2 on medications vs. 12.9 ⫾ 2.6 off medications), or number of episodes where pH ⬍ 4 (3.4 ⫾ 0.3 on medications vs. 3.7 ⫾ 0.5 off medications) (42). Chronic bronchodilator therapy did not adversely affect LES pressure or esophageal acid contact time (42). Field et al. examined GERD symptoms in 109 consecutive asthmatics (41). Ninety-three percent of asthmatics used β2-adrenergic agonists, 84% used inhaled corticosteroids, and approximately 33% used oral corticosteroids or theophylline (41). None of the asthma medications were associated with an increased likelihood of having heartburn or regurgitation (41). Although these studies show that patients on bronchodilators have no increase in GERD symptoms, esophagitis or esophageal acid contact times compared to asthmatics not on routine bronchodilators, they cannot conclude that bronchodilators do not influence an individual patient’s GERD, since individuals were not studied on and off bronchodilators. F. Conclusions

In conclusion, there are many physiologic alterations associated with asthma that may promote GERD. Factors controlling the competence of the gastroesophageal junction may be altered during an asthma attack. Normally, gastric pressure is positive in relation to pleural and esophageal pressure because the latter structures are in the chest (44). With increased airflow obstruction during an asthma attack, very negative pleural pressures can increase the pressure gradient between the thorax and abdominal cavity, predisposing the patient to develop reflux (47). The diaphragmatic crura contributes to pressure generation of the LES and may be altered in asthmatics (44). Overinflation and air trapping may also lead to flattening of the diaphragm, further impairing the antireflux barrier (66). Asthmatics with GERD have autonomic dysfunction, which may predispose asthmatics to develop GERD since the vagus nerve innervates the esophagus and vagal input influences LES pressure and esophageal motility (19). Bronchodilator medications may be detrimental to the competency of the gastroesophageal junction, especially theophylline and other methylxanthines, which increase gastric acid secretion and decrease LES pressure (67–69). There is continued debate about the influence of bronchodilator medications on the severity of GERD. Theophylline has the highest potential to produce GERD in asthmatics. Inhaled β2-adrener-

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gic agonists probably have minimal effect on esophageal parameters (77). Airway disease in asthmatics with GERD should be treated aggressively with antiinflammatory agents and bronchodilators. If possible, theophylline and oral β2adrenergic agonists should be avoided. Data also support that bronchodilators do not alter reflux symptoms or esophageal parameters (41,42,61). III. Lessons from Clinical Experience with Acid Suppression Many clinical investigations have examined whether antireflux therapy improves asthma outcome. Many studies have looked at predictors of asthma response. These predictors shed light on the pathophysiologic mechanisms of acid-induced bronchoconstriction (Table 3). One possible predictor of asthma response in asthmatics with GERD is endoscopic healing of esophagitis with antireflux therapy. This point was brought out by Meier et al., who performed a prospective double-blind crossover study examining 15 asthmatics with GERD (81). Using omeprazole 20 mg twice a day for 6 weeks, with an endpoint of a greater than a 20% net change in FEV1, they found that 4 of 15 patients had omeprazole-responsive asthma. They noted that only patients with complete endoscopic healing of esophagitis had omeprazoleresponsive asthma ( p ⬍ 0.01) (81). That healing of esophagitis is necessary for asthma improvement points out that esophagitis may play a significant role in reflux-associated bronchoconstriction. Acid reflux into the distal esophagus where esophagitis is present could stimulate acid-sensitive receptors inducing a vagally mediated reflex. One of the most respected studies in the literature examining asthma response was performed by Larrain et al. (82). They performed a prospective placebo-controlled trial where 90 nonallergic adult-onset asthmatics with less than Grade 1 esophagitis were randomized to receive cimetidine 300 mg four times a day, placebo, or a modified posterior gastropexy. After 6 months, more than 75% of the patients in the two therapy groups had a significant decrease in pulmo-

Table 3 Predictors of Asthma Response 1. 2. 3. 4. 5. 6. 7. 8.

Healing of esophagitis with antireflux therapy (81,82) Difficult-to-control asthma (83) History of reflux-associated respiratory symptoms (84,86) Intrinsic asthma (85) Onset of reflux symptoms before respiratory symptoms (85) Normal esophageal motility (86) Abnormal amounts of proximal esophageal acid (87,88) Presence of regurgitation (88)

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nary symptoms and medication usage scores (82). This study shows that nonallergic asthmatics without endoscopic evidence of esophagitis or grade 1 esophagitis had asthma improvement with aggressive antireflux therapy. Again, the role of healing of esophagitis is implicated. Irwin et al. prospectively examined difficult-to-control asthmatics requiring prednisone and implemented a systematic management protocol (83). They found that GERD was a possible contributing factor in 25 of 31 (81%) patients and 64% had a favorable asthma response with antireflux therapy (83). Also, GERD was clinically ‘‘silent’’ in 24% of patients. They concluded that difficult-to-control asthmatics need to be investigated for GERD, since therapy of reflux may improve asthma outcome (83). Ekstro¨m et al. performed a prospective double-blind crossover study on 48 moderate to severe asthmatics with GERD and treated them with ranitidine 150 mg twice a day for 4 weeks (84). They found that a history of reflux-associated respiratory symptoms predicted asthma improvement resulting in a significant decrease in nighttime asthma symptom score and a decrease in the number of metered dose inhaler puffs used per day (84). This implicated the importance of GERD and pulmonary symptom correlation in predicting a favorable asthma response. Perrin-Fayolle et al. reported a retrospective study examining asthma improvement in 44 asthmatics with GERD who were more than 5 years status postNissen transabdominal gastropexy (85). Subjects who were younger in age had nocturnal asthma attacks, and those with intrinsic asthma had improved asthma outcome (85). The onset of reflux symptoms before respiratory symptoms, severe GERD, and medical therapy response also predicted asthma improvement (85). DeMeester et al. performed a prospective study in 17 patients with pulmonary symptoms unresponsive to medical antireflux therapy who underwent fundoplication (86). Of 17 patients, 9 were free of respiratory symptoms in the postoperative state. Asthma success rate was higher in subjects who had normal esophageal motility. Seven of nine (78%) patients with normal esophageal motility preoperatively denied respiratory symptoms postoperatively, while only 2 of 8 (25%) patients with reflux with abnormal esophageal motility denied respiratory symptoms postoperatively (86). There was also a correlation between pulmonary symptoms and esophageal reflux events. Patients with pulmonary symptoms during or within 3 minutes of a reflux event had higher success rates than other patients (86). This was the first study that showed that 24-hour esophageal pH monitoring may predict which patients have improvement in asthma symptoms with aggressive antireflux therapy (86). The role of 24-hour esophageal pH monitoring in predicting asthma outcome was also noted in a study performed by Schnatz et al. who retrospectively examined 54 patients with cough or asthma triggered by gastroesophageal reflux (87). Patients received H2 blockers, omeprazole, surgery, or lifestyle therapy only

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for therapy of GERD. They found that 71% of subjects had good pulmonary symptom response with antireflux therapy (87). Nine of 11 (82%) with distal only esophageal reflux had a favorable response. Likewise, 4 out of 4 (100%) with proximal only reflux had a favorable response. Of patients with both distal and proximal reflux, 11 of 19 (58%) had improvement in pulmonary symptoms (87). None of the five patients who had normal esophageal acid contact times had pulmonary improvement. This study indicates that the presence of distal and proximal reflux may predict a favorable asthma outcome with antireflux therapy and that normal esophageal acid contact times may indicate that asthma symptoms will not respond to antireflux therapy (87). Our laboratory performed a prospective study examining predictors of asthma response in 30 asthmatics with GERD measuring asthma symptoms— peak expiratory flow rates before and after 3 months of documented acid suppression therapy with omeprazole (88). Asthma response was defined by a priori definition with an asthma symptom score reduction of greater than 20%. Twenty of 30 (67%) subjects were asthma symptom responders (88). Predictors of asthma response were identified by comparing demographic and esophageal variables in the asthma symptom responders and the nonresponders. Higher amounts of total proximal reflux, higher baseline asthma symptom score, higher baseline reflux symptom score, the presence of regurgitation, asthma exacerbated by upper respiratory tract infection, and asthma exacerbated by allergy showed a trend toward asthma improvement (88). In a forward stepwise logistic regression analysis examining models to predict asthma outcome, the presence of regurgitation more than once a week or excessive proximal reflux (defined as a greater than 1.1 percentage of time where esophageal pH was less than 4) predicted a greater than 20% improvement in asthma symptoms (88). The presence of regurgitation or excessive proximal reflux identified all responders with a 100% sensitivity. These findings were absent in all nonresponders, giving a 100% negative predictive value, a specificity of 44%, and a positive predictive value of 79% (88). Proximal esophageal reflux and regurgitation may be associated with microaspiration. In conclusion, there are many possible predictors of asthma response (Table 3). These include the presence of regurgitation as documented by Harding et al. and the presence of proximal esophageal acid in 24-hour pH monitoring documented by Harding et al. and Schnatz et al. (87,88). Nonallergic asthma also seems to be a possible predictor of asthma response as documented by Larrain et al. and Perrin-Fayolle et al. (82,85). Complete healing of esophagitis was important in Meier et al.’s study, as well as less than Grade 1 esophagitis in Larrain et al.’s study (81,82). Irwin et al. found that reflux may play a significant role in difficult-to-control asthmatics (83). Ekstro¨m et al. showed that reflux-associated respiratory symptoms may predict asthma response (84). Nocturnal asthma may also be a predictor, as is the onset of GERD symptoms before respiratory symp-

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toms, as documented by Perrin-Fayolle et al. (85). These predictors show that multiple pathogenic mechanisms may be responsible for airway responses to esophageal acid. Regurgitation and proximal esophageal acid may signify the role of microaspiration, and healing of esophagitis and reflux-associated respiratory symptoms may implicate a vagally mediated reflex. Further research will illustrate how GERD and airway disease interact.

Acknowledgments The author wishes to acknowledge Mr. Martin M. Robbins for his invaluable assistance in editing this manuscript, Dr. Joel Richter for his insight, and Drs. K. Randall Young and Jeffrey Hawkins for their support. Dr. Harding is supported by a Sleep Academic Award through the National Heart, Lung, and Blood Institute.

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64. Mittal RK, Holloway RH, Penagini R, Blackshaw LA, Dent J. Transient lower esophageal sphincter relaxation. Gastroenterology 1995; 109:601–610. 65. Mittal RK, Rochester DF, McCallum RW. Electrical and mechanical activity in the human lower esophageal sphincter during diaphragmatic contraction. J Clin Invest 1988; 81:1182–1189. 66. Roussos C, Macklem PT. The respiratory muscles. N Engl J Med 1982; 307:786– 797. 67. Foster LJ, Trudeau WL, Goldman AL. Bronchodilator effects on gastric acid secretion. JAMA 1979; 241:2613–2615. 68. Johannesson N, Andersson KE, Joelsson B, Persson CGA. Relaxation of lower esophageal sphincter and stimulation of gastric secretion and diuresis by antiasthmatic xanthines. Am Rev Respir Dis 1985; 131:26–31. 69. Stein MR, Towner TG, Weber RW, Mansfield LE, Jacobson KW, McDonnell JT, Nelson HS. The effect of theophylline on the lower esophageal sphincter pressure. Ann Allergy 1980; 45:238–241. 70. Berquist WE, Rachelefsky GS, Kadden M, Siegel SC, Katz RM, Mickey MR, Ament ME. Effect of theophylline on gastroesophageal reflux in normal adults. J Allergy Clin Immunol 1981; 67:407–411. 71. Ekstro¨m T, Tibbling L. Influence of theophylline on gastro-esophageal reflux and asthma. Eur J Clin Pharmacol 1988; 35:353–356. 72. Hubert D, Gaudric M, Guerre J, Lockhart A, Marsac J. Effect of theophylline on gastroesophageal reflux in patients with asthma. J Allergy Clin Immunol 1988; 81: 1168–1174. 73. Stein MR. Effect of theophylline on gastroesophageal reflux (letter). J Allergy Clin Immunol 1990; 85:140–141. 74. Mansfield LE. Effects of theophylline in gastroesophageal reflux (letter). J Allergy Clin Immunol 1989; 84:407–408. 75. Christensen J. Effects of drugs on esophageal motility. Arch Intern Med 1976; 136: 532–537. 76. DiMarino AJ, Cohen S. Effect of an oral beta-2 adrenergic agonist on lower esophageal sphincter pressure in normals and in patients with achalasia. Dig Dis Sci 1982; 27:1063–1066. 77. Schindlbeck NE, Heinrich C, Huber RM, Muller-Lissner SA. Effects of albuterol (salbutamol) on esophageal motility and gastroesophageal reflux in healthy volunteers. JAMA 1988; 260:3156–3158. 78. Michoud MC, Leduc T, Proulx F, Perreault S, DuSouich P, Duranceau A, Amyot R. Effect of salbutamol on gastroesophageal reflux in healthy volunteers and patients with asthma. J Allergy Clin Immunol 1991; 87:762–767. 79. Bittinger M, Barnert J, Weinbech M. Dose-dependant relationship between gastroesophageal reflux (GER) and inhalative therapy with fenoterol in chronic obstructive lung disease (COLD)-a preliminary report. Dis Esophagus 1994; 7:276–279. 80. Ruzkowski CJ, Sanowski RA, Austin J, Rohwedder JJ, Waring JP. The effects of inhaled albuterol and oral theophylline on gastroesophageal reflux in patients with gastroesophageal reflux disease and obstructive lung disease. Arch Intern Med 1992; 152:783–785. 81. Meier JH, McNally PR, Punja M, Freeman SR, Sudduth RH, Stocker N, Perry M,

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83. 84.

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Harding Spaulding HS. Does omeprazole (Prilosec) improve respiratory function in asthmatics with gastroesophageal reflux? A double-blind, placebo-controlled crossover study. Dig Dis Sci 1994; 39:2127–2133. Larrain A, Carrasco E, Galleguillos F, Sepulveda R, Pope CE, II. Medical and surgical therapy of nonallergic asthma associated with gastroesophageal reflux. Chest 1991; 99:1330–1335. Irwin RS, Curley FJ, French CL. Difficult-to-control asthma: contributing factors and outcome of a systematic management protocol. Chest 1993; 103:1662–1669. Ekstro¨m T, Lindgren BR, Tibbling L. Effects of ranitidine therapy on patients with asthma and a history of gastroesophageal reflux: a double blind crossover study. Thorax 1989; 44:19–23. Perrin-Fayolle M, Gormand F, Braillon G, Lombard-Platet R, Vignal J, Azzar D, Forichon J, Adeleine P. Long-term results of surgical therapy for gastroesophageal reflux in asthmatic patients. Chest 1989; 96:40–45. DeMeester TR, Bonavina L, Iascone C, Courtney JV, Skinner DB. Chronic respiratory symptoms and occult gastroesophageal reflux: a prospective clinical study and results of surgical therapy. Ann Surg 1990; 211:337–345. Schnatz PF, Castell JA, Castell DO. Pulmonary symptoms associated with gastroesophageal reflux: use of ambulatory pH monitoring to diagnose and to direct therapy. Am J Gastroenterol 1996; 91:1715–1718. Harding SM, Richter JE, Guzzo MR, Schan CA, Alexander RW, Bradley LA. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med 1996; 100:395–405.

8 Medical Treatment of Gastroesophageal Reflux Disease and Airway Disease

MANI S. KAVURU and JOEL E. RICHTER The Cleveland Clinic Foundation Cleveland, Ohio

I. Introduction There is a substantial literature that suggests a relationship between gastroesophageal reflux disease (GERD) and bronchial asthma (1). The possible associations between these two conditions are several (2): 1. These are two very common diseases that coexist independently in some patients. 2. Gastroesophageal reflux either exacerbates or is causally related to the pathogenesis of asthma in a subset of patients. 3. Bronchial asthma and/or antiasthma medications exacerbate or induce gastroesophageal reflux disease. It is likely that all three of these possibilities occur in subsets of patients with bronchial asthma. The magnitude of the association between GERD and asthma and its clinical significance remains unclear from the literature. Gastro esophageal reflux, with its primary symptoms of heartburn and acid regurgitation, is very common in the general population. A recent random sample of 2200 Olmstead County, Minnesota, residents aged 25–74 years found that 20% of the respondents had reflux symptoms at least weekly and nearly 60% had experienced 179

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either heartburn or acid regurgitation within the past year (3). The prevalence of GERD in asthmatics is reported to range from 34 to 89% (4–8). Reasons for this wide variability include the use of self-reported questionnaire data (9), comorbid confounding factors (alcohol, cigarette smoking, gender) (8,10), and the variability of definition and choice of diagnostic techniques to establish GERD (11). This chapter will assume that a relationship exists between GERD and asthma and will review various medical treatments for GERD and their effects on asthma symptoms, pulmonary function studies, and the need for asthma medications. An explosion of information has recently implicated airway inflammation in the pathogenesis of airway hyperreactivity in asthma (12). However, even though our understanding of the pathogenesis of asthma has increased in the past decade, so has asthma morbidity and mortality. Although several possible reasons have been offered for these trends, there appears to be a general consensus that suboptimal use of conventional asthma therapy by both patients and physicians plays an important role. The most recent asthma practice guidelines (National Asthma Education and Prevention Program, Expert Panel Report II) stressed the importance of chronic maintenance anti-inflammatory therapy in all patients with persistent asthma, along with educational and avoidance measures (13). Literature suggests that a subset of asthmatics have suboptimal asthma control, based on symptoms and need for acute health care services, despite maximal conventional therapy (12). It is likely that GERD plays a role in a subset of these asthmatics as well (14). A number of relevant issues exist regarding therapy for GERD associated with asthma. What are the clinical data showing the effectiveness of each type of medical therapy? Which group of asthmatics should receive therapy for GERD? Is empiric medical therapy for GERD-related asthma adequate, or are specific diagnostic tests followed by therapy more appropriate? For long-term maintenance therapy, what are the goals and what are the key outcome parameters? What is the optimal dose, duration, and agent for therapy? What are the long-term costs of no therapy versus the costs of medical therapy? With suboptimal asthma control, is it better to increase chronic asthma maintenance therapy and/or add therapy for GERD?

II. Methodology Issues A number of methodologic limitations exist in the published literature relating GERD and asthma (Table 1). The major limitation in all the published studies is the lack of attempt to optimize conventional, ‘‘standard’’ therapy for the underlying asthma. Today this means the use of daily inhaled corticosteroids (15). Inadequate use of inhaled corticosteroids is a major treatment shortcoming for

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Table 1 Methodologic Limitations of Studies Relating GERD and Asthma Lack of attempt to optimize conventional asthma therapy Lack of objective assessment or documentation of acid suppression Absence of a control group Small number of patients Outcome parameters for asthma control are not consistent Studies only involve patients with symptomatic GERD

many patients with poorly controlled asthma. The study of a ‘‘novel’’ intervention for GERD-related asthma without instituting conventional asthma therapy is an important source of variability in the published studies. A second major limitation in most studies is the lack of objective assessment of acid suppression while asthmatic patients are being treated for GERD. In the absence of documented control of acid reflux, one cannot conclude that therapy for GERD did not improve the associated asthma. A third limitation is the absence of a control group in some studies. Based on data from a variety of experimental antiinflammatory therapies for chronic ‘‘steroid-dependent’’ asthma, it is known that the placebo arm of these asthma studies could improve 20–40% simply by participating in a clinical trial, i.e., the ‘‘Hawthorne effect’’ (12). A fourth limitation is that the total number of asthmatics subjected to GERD therapy is quite small (77 patients in five reports for omeprazole and 125 patients in five reports for H2-receptor antagonists). Any beneficial effects of antireflux therapy associated with a small improvement in asthma control might not have been detected because of small sample size (β-error). A fifth limitation is that the choice of outcome parameters for asthma improvement are not consistent in the published studies. The beneficial effect on symptom scores has been much greater than other objective parameters, such as peak expiratory flow or forced expiratory volume in one second (FEV1). Finally, it is important to note that all published trials on therapy for GERD-associated asthma involve asthmatics with symptoms of heartburn or acid regurgitation. Therefore, findings cannot be extended to asthmatics with so-called ‘‘silent GERD,’’ where the reflux disease is diagnosed by a positive pH probe or endoscopic evidence of esophagitis in the absence of GERD symptoms. This chapter will assume that a relationship exists between GERD and asthma and that there is a need for aggressive treatment of the reflux disease to better control the asthma. We will limit our discussion to studies of adults with bronchial asthma and not include atypical presentations of GERD such as cough. Interventions to be considered will include lifestyle changes, antacids, alginic acid, H2-receptor antagonists, pro-kinetic agents, and acid proton pump inhibitors.

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The primary goal of managing GERD with or without associated extraesophageal disease is complete symptom resolution (16–19). Additional therapeutic endpoints include healing of esophagitis when present, prevention of complications such as peptic stricture or Barrett’s esophagus, and the maintenance of symptom control in patients with chronic disease. The overall management strategies can be classified as lifestyle changes, pharmacologic manipulations of gastric acid and motility, or surgery. See Table 2 for a summary of antireflux medications. A.

Lifestyle Modifications

Lifestyle changes include eating smaller meals and avoiding the supine position soon after meals, dietary modification to avoid certain types of foods as well as alcohol, weight reduction, smoking cessation, and elevation of the head of the bed for sleep. The lifestyle changes are intuitively appealing to physicians since they do not have side effects. These changes have other obvious medical benefits; they are within the ‘‘patient’s control,’’ and these changes are ‘‘simply the right thing to do.’’ Although all patients could be counseled about these lifestyle changes, the reality is that probably only a small subset of patients experiences significant relief with these interventions alone (20). Data to support each of these recommendations are, in fact, fairly limited.

Table 2 Antireflux Medications for the Treatment of GERD Antacids Alginic acid (Gaviscon) H2-receptor antagonists Cimetidine (Tagamet) Famotidine (Pepcid) Nizatidine (Axid) Ranitidine (Zantac) Prokinetic agents Metoclopramide (Reglan) Bethanechol (Urecholine) Domperidonea Cisapride (Propulsid) H⫹ /K⫹-ATPase (proton pump) inhibitors Omeprazole (Prilosec) Lansoprazole (Prevacid) Pantoprazolea a

Currently not available in the United States.

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Nocturnal acid reflux can be particularly damaging, as the normal acidclearance mechanisms are impaired. Gravity is not effective, as we usually sleep in the supine or prone position. During sleep esophageal peristalsis is minimal and saliva (pH 6.8–7.4) is not made—the reason we awaken with a ‘‘cotton mouth or dry mouth’’ in the morning. Limited data suggest that elevating the head of the bed 6–8 inches protects the esophagus from acid reflux during sleep (21,22). Placing pillows under the head is usually not enough; the head and upper body elevation typically requires placement of a foam wedge underneath the mattress or blocks underneath the headboard to elevate the entire bed. The impact of this maneuver reduced the time of esophageal pH ⬍ 4 from 22 to 14% in one study (21). This recommendation should target patients with nocturnal reflux symptoms and/or nocturnal asthma symptoms such as wheezing, chest tightness, and coughing. Cigarette smoking through the pharmacologic effect of nicotine contributes to GERD by decreasing lower esophageal sphincter (LES) pressure, increasing the frequency of reflux episodes, and decreasing acid clearance (23–25). Smoking cessation alone can significantly improve respiratory symptoms in patients with asthma. In the only study to investigate the impact of cessation of cigarette smoking on GERD, it was found that the immediate discontinuation of smoking decreased the number of daily reflux episodes but did not affect the total esophageal acid exposure in patients without esophagitis (26). Therefore, the contribution of cigarette smoking to GERD may only be modest; nevertheless, it should be recommended vigorously to all patients for the other overwhelming medical benefits. Patients who give a history of worsening reflux symptoms with certain foods should be counseled about avoiding these products. Foods can aggravate reflux symptoms by a number of mechanisms, including increased gastric volume producing gastric distention and transient LES relaxation, food contents directly lowering LES pressure, and direct irritant effects of food, possibly due to hyperosmolarity on inflamed esophageal mucosa (27). Fatty foods, alcohol, and chocolates are generally best avoided, especially prior to assuming the supine position (28,29). Also, a variety of medications, both prescribed and over-the-counter, can lower esophageal sphincter pressure and have direct effects by producing gastric and esophageal mucosal damage. Drugs in the former group include progesterone, theophylline (30–32), several prostaglandins, anticholinergic drugs, oral β-adrenergic agonists (33), α-adrenergic agonists, dopamine, diazepam, meperidine, morphine, and calcium channel blockers. Medications commonly causing direct injury to the esophagus include doxycycline, slow-release potassium, ascorbic acid, ferrous sulfate, aspirin, nonsteroidal anti-inflammatory drugs, quinidine, and alendronates. It appears that inhaled β-agonists such as salbutamol do not affect esophageal function (33,34). Whether obesity actually contributes to GERD and whether weight loss has beneficial effects is unknown.

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Kjellen et al. studied the effect of conservative treatment of GERD in a group of 62 patients with asthma and symptomatic GERD (35). The intervention included lifestyle changes (avoid eating for 3 hours before bedtime, avoid aspirintype medications, elevate head of bed, finish meals with a glass of warm water) and Gaviscon. Study design was randomized allocation to an intervention group and a control group, but patients were not blinded to the treatment. All patients had esophageal dysfunction by a variety of studies (this study antedated esophageal pH testing). The esophageal symptoms improved in 87% of treatment group and 11% of control group. Baseline asthma, which was characterized as exogenous or endogenous, was treated with inhaled steroids in only 18 of 62 patients (29%). Improvement in asthma was statistically significant for the treatment group based on symptoms and need for β-agonists. However, there was no description of the validity of the questionnaire or how symptoms were scored. Also, the reduction in β-agonist use was from 4.4 to 3.8 puffs/day ( p ⬍ 0.05) for the treatment group and 3.9 to 3.6 puffs/day for the control group. Less than one puff reduction is probably not clinically significant, especially in patients who were not treated with inhaled steroids. Also, there was no significant improvement in objective pulmonary function studies. B.

Antacids/Alginic Acid

Used on an as-needed basis, antacids and alginic acid are the mainstay of rapid, safe, effective relief of heartburn symptoms. Antacids primarily work by neutralizing acid, albeit for relatively short periods of time. Therefore, patients need to take antacids frequently, usually 20–30 minutes after meals and bedtime, depending on the severity of symptoms. Liquid forms are preferable to tablets, although the latter are the most popular preparation of this medication. Containing antacids and alginic acid, Gaviscon is a popular over-the-counter treatment for GERD. The active component of this medication, alginic acid, interacts with saliva to form a highly viscous solution that floats on the surface of the gastric pool, acting as a mechanical barrier. The barrier reduces the number of reflux episodes and diminishes esophageal acid exposure during the day but not at night (36). Antacids and alginic acid are effective for relieving mild to moderate intermittent reflux symptoms (37,38). They are particularly useful in patients with situational heartburn brought on by lifestyle changes or pregnancy. Even in high doses, these agents are not effective in healing esophagitis. Excessive use of antacids may be associated with side effects. Magnesiumcontaining antacids produce diarrhea, while aluminum-containing products are constipating. The potential for magnesium or aluminum toxicity further limits their use in patients with significant renal disease. Low-sodium antacids (e.g., magaldrate-Riopan) are preferable for individuals on salt-restricted diets. Antacids and alginic acid are the initial agents of choice for treating reflux symptoms

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in pregnant women since they are nontoxic. In this special situation, adverse effects are rare but include interference with iron absorption, with ingestion of sodium bicarbonate, metabolic alkalosis and fluid overload in both the fetus and mother. C. H2-Receptor Antagonists

The four currently available H2-receptor antagonists (H2-RAs), cimetidine, ranitidine, famotidine, and nizatidine, act competitively and reversibly to inhibit stimulation of the parietal cell by histamine (39). The plasma concentration of the drug correlates approximately with the degree of inhibition. These agents block nocturnal acid secretion more effectively, having minimal effect on meal-stimulated acid secretion. H2-receptor antagonists have no significant effect on gastric emptying, LES pressure, or pancreatic secretion. Overall, H2-RAs decrease acid reflux by 30–50%. Standard doses of H2RAs given twice a day (morning and before supper) alleviate symptoms of GERD and heal mild to moderate erosive esophagitis. A recent summary of studies evaluating the treatment of GERD by H2-RAs suggests an aggregate symptomatic response in 1132 of 1887 patients (60%) and a healing rate for 506 of 1003 (50%) patients, compared to placebo rates of 27% and 24%, respectively (40,41). The typical duration for these studies ranges from 6 to 12 weeks. Some patients, failing a course of standard dose of H2-RAs, may be hypersecretors of acid; they may require higher and more frequent doses of the H2-RAs. Ranitidine is the only H2-RA approved for the maintenance healing of erosive esophagitis. The recommended dose is 150 mg twice daily, with placebo-controlled trials having been carried out for one year. All the H2-RAs are now available over the counter, usually at 50% the prescription dose. Their use is similar to that of antacids for the treatment of intermittent heartburn, although the rapidity of relief is not as good as with antacids. The over-the-counter H2-RAs are superior to antacids in preventing reflux episodes after large meals, exercise, or other provocative situations when given 30 minutes before the refluxogenic activity. The H2-RAs have an excellent side-effect profile and a low incidence of the following adverse reactions: central nervous system disturbances (especially cimetidine in high concentrations), headaches, diarrhea, gynecomastia, and impotence. Drug interactions (cimetidine binds to the cytochrome P-450 system with greater affinity than does ranitidine) include those with theophylline, warfarin, phenytoin, and benzodiazepines. Neither famotidine nor nizatidine interacts with the cytochrome P-450 system. The H2-RAs cross the placental blood barrier and are excreted in breast milk. A recent large case-control study in Canada, however, found no adverse side effects in pregnant women taking this class of drugs at any stage of pregnancy (42). Therefore, the H2-RAs can be used in pregnant

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women with very severe reflux symptoms not responding to lifestyle changes or antacids. Table 3 summarizes the adult studies with H2-RAs for asthma and GERD. These studies include four placebo-controlled crossover trials (43–46) and one case series (47) using either cimetidine or ranitidine. Goodall et al. conducted a placebo crossover trial of 20 adult asthmatics with GERD recruited from a pulmonary outpatient clinic (43). Cimetidine 200 mg 4 times a day or placebo was given over 6 weeks with a 1-week washout period. At baseline, 18 of 20 patients had abnormal acid reflux, by manometry and pH monitoring, reflux of barium, or endoscopy. On cimetidine, reflux symptoms improved significantly in 14 of 20 patients compared with placebo (a drop in GERD symptom score from 2.8 to 1.1, p ⬍ 0.02). Baseline asthma severity was probably mild to moderate. All patients had nocturnal asthma symptoms, but the baseline asthma therapy was not described. Despite effective treatment of the gastroesophageal reflux, there were only minimal changes in a variety of asthma outcome parameters. The daytime symptom score did not change, and the night score decreased slightly from 1.1 to 0.7, reaching statistical significance ( p ⬍ 0.05), but of uncertain clinical significance. Four peak flow readings were obtained per day, but only the night peak flow increased from 310 to 335 ( p ⬍ 0.05). There was no significant change in the FEV1, and no change in the use of rescue albuterol. Overall, this is essentially a negative trial, but the study limitations include the lack of documented control of GERD, a less than standard dose of cimetidine, and a relatively short duration of treatment. Harper et al. reported on 15 adult nonsmokers with symptomatic GERD, all of whom had pH testing (10 of 15 with erosive esophagitis, total reflux time of 22.5% with pH ⬍4) (47). Therapy was ranitidine 150 mg twice a day for 8 weeks. These were nonallergic asthmatics, only 4 of which had nocturnal asthma symptoms. Interestingly, some patients were pretreated at baseline with prednisone for the various procedures in this study. This could have artifactually increased the baseline FEV1, thereby lessening the degree of possible improvement. Within one week of beginning ranitidine therapy, there was significant reduction in heartburn and regurgitation scores, but significant improvement in pulmonary symptom scores took 7 weeks of therapy. Pulmonary function tests (PFTs), including FEV1, FVC, and percent of FEV1, were improved significantly after 8 weeks of therapy. Although not a placebo-controlled study, this study suggests that improvement of asthma may not immediately parallel improvement of esophageal symptoms but may take much longer. In a placebo crossover trial, Nagel et al. studied 44 adult asthmatics with esophageal pH testing (44). Twenty-one of the 44 patients had nocturnal asthma symptoms along with a drop in early morning peak flows (‘‘morning dipping’’). Fifteen of 44 patients (34%) also had GERD and were the subjects participating in this trial. Of the patients with GERD by pH testing (mean 20% of the time

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pH ⬍ 4), only seven had symptoms of heartburn or regurgitation. Ranitidine 450 mg a day or placebo was used only for 7 days with a 3-day washout. Asthma symptom scores improved in only 3 of 15 patients; there was no objective change in the peak flows or the need for rescue medications. This was a reasonable population of asthmatic patients to study, although the glaring study limitation is the very short duration of antireflux therapy and the absence of documented control of GERD. Ekstrom et al. recruited 48 asthmatics, all of whom had symptomatic GERD, from the outpatient medical clinic for a 4-week intervention with placebo or ranitidine 150 mg bid with a 2-week washout period (45). The severity of acid reflux was modest by pH testing (4.4% time pH ⬍4); 27 of 48 subjects had a positive acid perfusion test. The subjects had moderate-to-severe asthma that was well characterized, and 32 of 48 patients were documented to be on inhaled corticosteroids. Importantly, 20 of 48 patients were on oral prednisone therapy with a dose of about 6.5 mg per day. These authors showed symptomatic improvement in GERD but did not objectively assess reflux control. Overall, there was only a slight improvement in the nighttime asthma score, which was statistically significant at p ⫽ 0.02. There was no change in the morning or day symptom scores, nor objective changes in FEV1, peak flow, or histamine challenge studies. There was only a trivial reduction in inhaled β-agonist use. D. Promotility Agents

The newer promotility agents, cisapride and domperidone, are effective in the treatment of mild to moderate heartburn and healing mild erosive esophagitis. This class of drugs improves GERD by augmenting lower esophageal sphincter pressure, increasing the amplitude of esophageal peristalsis and thereby improving acid clearance, and accelerating gastric emptying or modifying duodenogastric reflux, if abnormal. The older agents, including metoclopramide and bethanechol, were not particularly effective and were frequently associated with central nervous system side effects. Recent data shows that cisapride at 10 mg four times a day (30 minutes before meals and bedtime) provides symptomatic relief and healing of esophagitis with results comparable to cimetidine 400 mg four times a day or ranitidine 150 mg twice a day and superior to placebo. Some data suggest there may be benefit combining the promotility agents with the H2-RAs (41). Additional data suggest that cisapride may be effective as maintenance therapy for mild GERD (48). Side effects are infrequent with cisapride and usually consist of abdominal pain, diarrhea, or headaches. Metoclopramide has been used safely as an antiemetic agent during pregnancy for about 30 years. A recent case-control study found no adverse effects on mother or child in pregnant women taking cisapride (49). This study included 129 pregnant women, 88 of whom took cisapride during the period of fetal organogenesis.

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Table 3 H2-Receptor Antagonists for Asthma and Gastroesophageal Reflux: Summary of Adult Studies Author, year (Ref.)

Design

N

Age (M/F)

Recruitment source

Duration of intervention (weeks)

Baseline GERD Dose

Dx

Severity

Goodall, 1981 (43)

Placebo crossover

20

54 (13/7)

Pulmonary outpatient clinic

6 weeks

Cim 200 mg 4x/ day

GERD Sx 19/20 18/20 had abnormal studies

?

Harper, 1987 (47)

Case series, pre-, postcomparison

15

48 (6/9)

N/S

8 weeks

Ran 150 mg bid

GERD Sx 15/15 10/15 erosive esophagitis

Total reflux scores 22.5% ⫾ 9.9%

Nagel, 1988 (44)

Placebo crossover

15

42 (11/4)

Pulmonary clinic

1 week, 3 days washout

Ran 450 mg/d

7/15 GERD Sx

pH ⬍ 4 20% time

Ekstrom, 1988 (45)

Placebo crossover

48

58 (30/18)

Outpatient medical clinic

4 weeks, 2 week run-in & washout

Ran 150 mg bid

48/48 GERD Sx

GERD ⬎ 1⫻/wk pH ⬍ 4 4.4% time 27/48 ⊕ acid-perf

Larrain, 1991 (46)

Placebo controlled 3-arm randomized trial

28 ⫽ plac 27 ⫽ exp

P: 42 (9/19) Exp: 43 (2/25)

Pulmonary clinic

6 months

Cim 300 mg 4x/d

P: 19/28 GERD Sx Exp. 19/27

N/S

Abbreviations: cim ⫽ cimetidine; ran ⫽ ranitidine; β-MDI ⫽ β-agonist metered dose inhaler; ICs ⫽ inhaled corticosteroids; N/S ⫽ not specified; FEV1 ⫽ forced expiratory volume in one second; PEF ⫽ peak expiratory flow; PC20 ⫽ provocative concentration of methacholine for 20% drop in FEV1; EGD ⫽ endoscopy; P: placebo; exp ⫽ experimental.

There are no published studies of promotility agents being used to treat adult asthmatics with GERD. An initial study in the pediatric literature assessed 29 infants (2–4 months old) with GERD by 24-hour pH monitoring (50). These babies were randomized to therapy with body positional treatment in addition to either placebo or cisapride. After 16 days of therapy, there was no significant

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Asthma outcome measures Baseline asthma Dx

Severity

Noctumal asthma 20/20

Documentation of acid control Rx

Mild-mod? N/A baseline FEV1 ⬃ 2.0; 17 years

Non-allergic Baseline N/S asthma FEV1 Nocturnal 72%, raasthma Sx tio 0.95 in 4/15

Sx

pH

Sx scope im- — proved in 14/20 c/w plac From 2.8 to 1.8 (p ⬍ 0.02) Improved Clear-cut imSx scores provement in EGD 10/10 Resolved in 8/10

Well established 21/44 had nocturnal asthma

N/S

N/S

No

Well established

Modsevere; 14 years

ICs ⫽ 32/48 GERD score No Theo ⬃ 26/48 improved Pred ⫽ 20/48 from 0.69 (dose ⬃ 6.5/ → 053 d) (p.0002) p.o β-MDI ⬃ 33/48

N/S

Duration: 10 years

P: 14/28 pred Exp: 13/27 NO ICs

N/A

No

N/A

Sx

PEF or FEV1

βMDI/ pred use

Comment

Night score ↓ed 1.1 →0.7 (p ⬍ 0.05) Day: NO ∆

x4/day FEV1 no ∆

No ∆ in βMDI

Increase in Sx for 4 weeks, then sig. decrease

Increase in FEV1 to 82% (p ⬍ .001)

Scores improved 3/15 deteriorated 5/15 6/15 → no ∆

No ∆ AM, PM PEF

Sight improvement in night asthma score 0.61 → 0.53 (p.02) No ∆ in AM or day score N/S

No ∆ in PEF, FEV1, PC20

Meds inNo good correlation becreased in tween changes in 6/15, deFEV1 & esoph Sx creased Some patients were pre3/15, untreated with pred bechanged fore procedures— in 4/15 FEV1 may have ↑ed No ∆ 44 adult asthmatics underwent pH test 21/44 → ‘‘morning dipping’’ with noct Sx, ↓ PEF 15/44 → GERD → participated in study (34%) No difference in GERD in patients with noct Sx c/w others β-MDI 350 asthma pts puffs/ N ⫽ w/asthma & day 5.6 GERD Sx ⬎ 1⫻/wk → 5.0 Most rep Sx improvement occurred in pts with hx reflux assoc. resp Sx (N ⫽ 27) 21 (No hx of refluxassoc. Sx) → no response N/S

N/S

change in the total number of reflux episodes or the number of reflux episodes per hour; however, there was a significant improvement in the number of reflux episodes lasting longer than 5 minutes (0.30 vs. 0.59, p ⬍ 0.01), suggesting that cisapride improves acid clearance. A second study evaluated the effect of cisapride on esophageal pH monitoring in children with reflux-associated cough (51). Over one month, there was a significant reduction in the cough episodes at night as well as GERD (time pH ⬍ 4 decreased from 18 to 4.9%). A third uncontrolled,

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open-label study included 36 children with poorly controlled asthma and no GERD symptoms (52). By pH test, 27 of 36 patients (75%) were documented to have GERD. All patients were treated with cisapride (0.2 mg/kg qid) for 3 months. A second pH test was performed on 11 of 27 patients, 9 of whom showed improvement in time pH ⬍ 4. Follow-up was conducted for 19 patients, 16 (84%) of whom had improvement in asthma symptoms. E.

Hⴙ /Kⴙ-ATPase (Acid Proton Pump) Inhibitors

Acid-forming parietal cells are located in the oxyntic glands of the gastric fundus and body (53). Parietal cell membrane consists of three classes of receptors: histamine, paracrine receptors; gastrin, endocrine receptors; and acetylcholine, neurocrine (muscarinic) receptors. All of these receptors mediate the final step in the secretion of hydrochloric acid through the activation of the H⫹ /K⫹-ATPase acid pump (Fig. 1). Antacids have no direct influence on gastric acid secretion. These agents work by neutralizing the gastric acid secreted by parietal cells, thereby increasing the intragastric pH. Both the H2-RAs and the acid proton pump inhibitors block acid secretion. The H2-RAs only block histamine receptors on the parietal cell surface, while the gastrin and acetylcholine receptors are still active and can augment acid secretion. On activation of the parietal cell, the enzyme H⫹ /K⫹ATPase moves from the cytoplasm of the gastric parietal cell to the permeable membrane of the secretory canaliculi (53). The enzyme can subsequently move hydrogen ions across the parietal cell membrane in exchange for potassium ions, thereby secreting acid with a pH of about 1.0. Both of the currently available substituted benzimidazoles, more commonly called proton pump inhibitors (omeprazole and lansoprazole), bind to the H⫹ /K⫹-ATPase enzyme, thus blocking acid secretion. Since both nocturnal and meal-stimulated acid is inhibited, a single morning dose maintains gastric pH at 5 or more for almost 24 hours, decreases gastric volume by over 60%, and normalizes acid reflux parameters in over 80% of patients (53–55). Proton pump inhibitors have no effect on LES pressure. In general, the proton pump inhibitors are well tolerated and easy to use with dosing either once or twice a day. Rare side effects include diarrhea, nausea, dry mouth, dizziness, weakness, headaches, and numbness. However, these side effects are no more common than with placebo in the published studies. Omeprazole inhibits selective isoenzymes of the cytochrome P-450 system, including those that metabolize phenytoin, warfarin sodium, and benzodiazepines (but not theophylline or propranolol). On the other hand, lansoprazole minimally inhibits this system and does not appear to significantly interfere with other drugs metabolized by cytochrome P-450 (56). The major long-term concern with using the proton pump inhibitors is their ability to produce a profound decrease in gastric acid secretion. This causes a secondary increase in gastrin production from the

Figure 1 Schematic diagram of a parietal cell: therapeutic modalities to affect gastric acid. Parietal cell membrane consists of three classes of receptors: acetylcholine, histamine, and gastrin. The final step in the secretion of hydrochloric acid is through the activation of ATPase acid pump. PGE2 ⫽ prostaglandin E2. Substituted benzimidazoles are proton pump inhibitors. See text for details.

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antral G cells resulting in serum gastrin levels usually elevated two to four times above basal values. Theoretically, the prolonged gastrin stimulation of enterochromaffin-like (ECL) cells could produce tropic changes in the gastric mucosa and was associated with increased stomach tumors in rats treated for a lifetime. However, the human experience with the use of proton pump inhibition is over a decade, with a number of patients with severe reflux esophagitis taking the drug continuously for up to 10 years. There have not been any reported cases of gastric carcinoid-type tumors in patients receiving either omeprazole or lansoprazole, with the rare exception of subjects with the multiple endocrine adenomatosis syndrome where carcinoid tumors are commonly seen. The consensus from published studies and close FDA surveillance of the proton pump inhibitors is that these drugs at therapeutic doses are unlikely to result in clinically significant gastric mucosal change (54–58). Several recent review articles have summarized the results of randomized trials with proton pump inhibition in the treatment of GERD (40,53). Controlled studies show that omeprazole 20 mg q AM or lansoprazole 30 mg q AM completely abolishes reflux symptoms in most patients with GERD, regardless of severity, usually within 5 weeks. Complete healing of esophagitis occurs after 8 weeks in more than 80% of patients (54,59,60). In those not healing after this time, prolonged therapy with the same dose or increasing the dose usually results in nearly 100% healing (58), although rare patients are resistant to doses of omeprazole up to 180 mg/day (61). Head-to-head comparison found no efficacy difference in either symptom relief or esophagitis healing between omeprazole or lansoprazole (60). Both proton pump inhibitors also are effective for maintaining the healing of esophagitis, regardless of severity, for up to 1 year in controlled studies and up to 5 years in case series (55,58). The maintenance dose of omeprazole is usually 20 mg/day, while lansoprazole 15 mg/day is as effective as 30 mg for long-term therapy. Proton pump inhibitors are the most effective medical therapy for treating GERD, with long-term results similar to antireflux surgery. Table 4 summarizes the available published adult studies of omeprazole therapy for asthma and associated GERD. Studies with lansoprazole have not been published. Available data include one case report (62), three placebocontrolled crossover trials (63–65), and one prospective case series with a pretest and posttest comparison (66). A case report by Depla et al. describes a 25-year-old man with wellestablished severe bronchial asthma with nocturnal symptoms (62). This patient’s maintenance asthma therapy included inhaled albuterol, ipratropium, beclomethasone (dose not specified), as well as oral terbutaline. Esophageal pH monitoring found severe GERD with pH ⬍ 4 for 27% of the time. The upper endoscopy was normal. The patient previously failed reflux therapy with ranitidine 750 mg per day. Omeprazole 20 mg a day was used for 12 weeks. There was dramatic improvement in GERD based on symptoms as well as a follow-up pH study

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showing the acid-exposure time decreasing to normal value (4%). From an asthma standpoint, there was definite improvement in symptoms, FEV1 (beforetherapy range was 2.85–3.81 liters; after-therapy value was 3.88 liters), and a reduction in the need for nocturnal rescue inhaler therapy. This single-case report well documents improvement in both GERD and asthma with the institution of omeprazole therapy. Ford et al. conducted a placebo-controlled crossover trial of 11 asthmatics, with a mean age of 63 years, recruited from an outpatient pulmonary clinic, with a history of asthma predating GERD (3.4 years vs. 6.4 months) (63). All patients had moderately severe bronchial asthma with nocturnal symptoms despite treatment with inhaled corticosteroids in 8 of 11 patients (dose not specified). All patients also had symptoms of GERD, an abnormal upper endoscopy, and a positive pH test in 9 of 11 patients. Patients were randomly assigned to initial therapy with omeprazole 20 mg per day or placebo, and after a one-week washout, they were crossed over to the other agent. Although reflux symptoms resolved in 5 of 10 patients on omeprazole therapy, there was no objective documentation of acid control by follow-up pH testing. Compliance with therapy was noted to be 96%. One patient was excluded secondary to uncontrolled asthma. There was no improvement in asthma control based on day or nighttime symptom scores, a.m. and p.m. peak expiratory flows, or any changes in the need for inhaled rescue bronchodilators. The strength of this study included well-characterized asthmatics, and most patients had continued respiratory symptoms despite being on maintenance therapy with inhaled corticosteroids. The obvious limitations included the short treatment duration, lack of documented reflux control, and perhaps an inadequate dose of omeprazole. Meier et al. conducted a 6-week placebo-controlled crossover study of 15 adult asthmatics with symptomatic GERD with a 2-week wash-in period and a 2-week run-in period (64). Omeprazole 20 mg twice a day was used. Patients were recruited from an allergy clinic from a database of 3000 asthmatics. Thirty of these patients had both asthma and weekly heartburn, of which 15 were selected for the study. All patients had well-established asthma, but there was no mention of nocturnal asthmatic symptoms nor a description of baseline asthma therapy. All subjects had moderately severe GERD with endoscopic esophagitis and an average distal acid exposure over 24 hours of 22%. Asthma outcome was described as omeprazole-responsive asthma based on a 20% improvement in FEV1 (4 of 15 or 27%) or non–omeprazole-responsive asthma (11 of 15 or 73%). Data regarding symptoms or medication use were not given. Follow-up endoscopy showed that all responders had endoscopic healing of esophagitis, whereas only 6 of 11 nonresponders showed esophagitis healing. Overall, this study suggests that a subset of asthmatics with GERD will respond to aggressive antireflux therapy. This subset may have been larger if there was titration of omeprazole dose to documented control of GER and/or a longer duration of therapy with

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Table 4 Omeprazole for Asthma and Gastroesophageal Reflux: Summary of Adult Studies Author, year (Ref.)

Design

N

Age (M/F)

Recruitment source

Smoking hx

Duration of intervention (weeks)

Baseline GERD Dose

Dx

Severity

Depla, 1988 (62)

Case report 1 25 (M)

N/S

N/S

12 weeks

20 mg qd

Normal EGD ⊕ pH test

pH ⬍ 4 27% time Severe

Ford, 1994 (63)

Placebo 11 63 (6/5) crossover

Pulmonary OPD

2/11

4 weeks, with 1 week run-in, washout

20 mg qd

11/11 EGD 9/11 pH test 11/11 Sx

N/S

Meier, 1994 (64)

Placebo 15 49 (9/6) crossover

Allergy clinic None Database of 3000 asthma 30 ⫽ asthma & weekly pyrosis 15 ⫽ met criteria Outpatient pulmo- None nary medical clinics

N/S

EGD esophageal and/or distal pH ⬍ 4 22% time

Harding, 1996 (65)

Prospective 30 46 (12/ case se18) ries, pretest & posttest comparison Teichtahl, Placebo 20 46 (12/8) Outpatient None 1996 crossover pulmonary/ (66) gastroenterology clinics

6 weeks, 2 weeks run-in, 20 mg washout bid

4 weeks pre-therapy 20–60 29/30 (97%) had inSx ⱖ 2x/mo phase; 4–12 weeks acid mg/d creased distal acid re- pH ⬍ 4 titration phase; 3 mos flux; 1 only abn proxi12.1% acid suppressive doses mal reflux time

4 weeks, with 2 weeks run-in, washout

40 mg/ 19/20 had GERD Sx d

pH ⬍ 4 12% time

FEV1 ⫽ Forced expiratory volume in one second; EGD ⫽ endoscopy; Sx ⫽ symptoms; PEF ⫽ peak expiratory flow; ORA ⫽ omeprazole responsive asthma; terb ⫽ terbutaline; beclo ⫽ beclomethasone; ICs ⫽ inhaled corticosteroids; β-MDI ⫽ β-agonist metered dose inhaler; N/S ⫽ not specified.

complete esophagitis healing in the additional 5 patients. This is particularly relevant in this study as the nonresponders had two to three times the amount of distal or proximal GER compared to the responders. However, this study also confirms that some patients with asthma and symptomatic GERD may not improve their asthma despite good control of reflux symptoms and healing of esophagitis. The largest study to date, as well as the most compelling data for treating GERD in asthma, was published by Harding et al. involving 30 adult asthmatics with GERD (65). This study included 18 women and 12 men (mean age 46 years), who were recruited from the outpatient pulmonary and medical clinics for this prospective, open-label case series with pretest and posttest comparisons of the effects of therapy. All patients had control of acid reflux documented by serial pH testing using doses of omeprazole ranging between 20 and 60 mg/day. There was a 4-week run-in period, followed by a period of 4–12 weeks for acid titration,

Medical Treatment of GERD

Documentation of acid control

Baseline asthma Dx

Severity

195

Rx

Sx

pH

Albuterol Yes Yes (4% pH ⬍) Ipratropium P.O. terb Beclo (? dose) Well estab- Moderate ICs ⫽ 8 PRN No GER Sx No lished β-MDI in 5/10 on ⊕ nocturomep nal Sx Well estab- Severe lished Nocturnal Sx

Well estab- N/S lished No mention of nocturnal Sx Well established No mention of nocturnal Sx

Well established ⊕ nocturnal Sx

N/S

0

Asthma outcome measures β-MDI pred use

Sx

PEF or FEV1

Improved

FEV1 2.85– 3.81 before; 3.88 after

Night: 0: 1 ⫾ 0.6 P: 1 ⫾ 0.7 day O: 1 ⫾ 0.7 P: 0.9 ⫾ 0.7

AM PEF: O ⫽ 262 ⫾ 86 P ⫽ 255 ⫾ 86 PM PEF: O: 280 ⫾ 81 P: 277 ⫾ 78 4/15 ⫽ ORA N/S FEV1 ↑ed 20%

Comment

↓ Nocturnal βMDI

All 4/15 om-resp. N/S had complications esop. head 6/11 non-ORA showed complete history ModICs ⫽ 16/30 Yes Yes (titration Sx score (0– 6/30 (20%) 5/30 (17%) were severe Pred ⫽ 15/30 Sx score omep for acid 105) dewere PEF re- med usage re(77%) Mean ⫽ 3 (0–84) de- supp) creased from sonders (PEF sponders; 4/15 FEV1 meds creased 32.2 to 19.0 increase of (27%) were 72% from 21.4 20/30 were Sx 20%) able to reduce → 3.7 responders dose of pred ⬎ 40% FEV1 70 Stable Rx for Improved in No No change in AM PEF No change ⫾7% 1 mo. beomep Sx 76 ⫾ 4 vs. 76 fore group c/w ⫾ 4% ICs: 21/25 placebo (p PM PEF Pred: 3 ⬍ .05) 82⫾ Theo: 9

1 pt excluded 2° to uncontrolled asthma Asthma: 3.4 mos; GERD 6 mos. 10/15 had complete healing; all ORA were complete healers Overall 27% pts ORA Spiro Sensormedics Morris/Polgar ? what is size of screened population, time. 30/38 completed Asthma: 275 mos; GERD: 83 mos

followed by 3 months of therapy with acid-suppressive dosages. All patients had reflux symptoms at least weekly, with 97% of the patients having increased distal acid reflux, mean total acid reflux 12.1% (normal ⬍ 5.8%). With acid suppression, the GERD symptom score dramatically improved from 21.5 to 3.7. The underlying asthma in these nonsmokers was fairly well characterized as being moderately severe; however, there was no mention of the frequency of nocturnal symptoms. At baseline, patients used a mean of three asthma medications, including inhaled corticosteroids in 16 of 30 patients and oral prednisone in 15 of 30 patients. Follow-up evaluation also showed that proton pump inhibitor therapy was effective in improving asthma control. The asthma symptom score (a range of 0 to 105) improved from 32 to 19, and 20 of 30 patients (66%) were found to have at least a 20% improvement in asthma symptoms. Lung function responders were defined as having a peak flow increase of 20% from baseline; this was

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seen in 6 of 30 patients (20%). The use of asthma medication decreased in 5 of 30 patients (17%), and 4 of 15 (27%) asthmatics were able to reduce their dose of prednisone by greater than 40%. Further analysis showed that the presence of regurgitation (⬎1 per week) or excessive proximal esophageal reflux predicted asthma response to omeprazole therapy at 100% sensitivity and a positive predictive value of 79%. The strength of this study lies in the fact that control of acid reflux was accomplished in all patients with omeprazole therapy. Also, the duration of therapy for GERD and asthma was the longest to date. The authors noted that 27% of the patients required more than 20 mg per day of omeprazole to accomplish acid suppression, 6 patients needed 40 mg, and 2 patients required 60 mg per day. Although the mean symptom score improved significantly in the group as a whole, some asthmatics improved much more dramatically (5 of 30 patients had a symptom score improve by greater than 50 points). On the other hand, the objective improvement in lung function was disappointing and clinically modest (only 6 of 30 patients had a peak flow increase of greater than 20%). This study needs to be repeated using a control group of subjects. Teichtahl et al. conducted a placebo-controlled crossover trial for an intervention period of 4 weeks (omeprazole 40 mg) with a 2-week run-in and a 2week washout (66). Twenty adults with asthma and GERD were recruited from outpatient pulmonary and gastroenterology clinics. Actually, 30 patients entered the run-in, 25 were randomized, and 20 finally completed the study. All patients had GERD symptoms, and a baseline pH test showed an average acid exposure time with pH ⬍4 of 12%. Baseline asthma was well characterized as moderate disease, and all patients had nocturnal symptoms. The disease was stable for one month before the study and inhaled corticosteroids were appropriately administered in 21 of 25 patients, an additional 9 patients took theophylline and 3 patients were taking oral prednisone. The mean duration for asthma was much longer than GERD (275 months vs. 83 months). Compliance was greater than 75%. GERD symptoms were improved in the omeprazole group compared to the placebo group ( p ⬍0.05). However, there was no other documentation of acid control to assess the adequacy of dose or duration. As far as the effect on asthma is concerned, this is a negative trial as there was no change in any of the asthma-outcome measures, including symptoms, peak flows, FEV1, airway reactivity, or the use of medications. Again, one wonders whether there was adequate control of acid reflux and whether the duration of therapy was sufficient.

IV. Surgical Therapy The published experience with antireflux surgery for GERD in adult patients with asthma is summarized in Table 5 (46,67–71). Most of the surgical trials have a

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variety of design flaws including lack of a control group, poor documentation of airflow obstruction both preoperatively and postoperatively, poor documentation of baseline asthma severity and baseline asthma medical therapy, and lack of objective documentation of GERD control in the postoperative state. Although proton pump inhibitors can relieve GERD symptoms and heal esophagitis in the vast majority of patients, this has not eliminated the need to consider surgery in a subset of patients (72). In fact, a good response to medical therapy may help to identify the subset of patients who will do well after surgery (73). Antireflux surgery should be reserved for patients with complicated GERD who will require lifetime medical therapy (74). Some indications for surgery include: (1) patient requires lifelong therapy with high-dose H2-RAs or proton pump inhibitors, (2) refractory reflux disease with intolerable symptoms or esophagitis that has proved difficult to treat, (3) recurrent esophageal strictures, (4) esophagotracheal aspiration resulting in recurrent pneumonia, asthma, or laryngitis, or (5) bleeding from Barrett’s ulcers or as a result of a hiatal hernia causing linear gastric erosions (72). Several preoperative factors influence whether and what kind of surgery is beneficial: (1) functional status of the lower esophageal sphincter and esophageal pump as assessed by the adequacy of peristalsis, (2) esophageal length, (3) presence of acid hypersecretion, (4) degree of delayed gastric emptying, and (5) relative surgical risk based on age and comorbid diseases. Further discussion about the specific surgical procedures will be considered elsewhere (see Chap. 9). Two studies attempted to compare medical and surgical therapy for GERD in patients with both asthma and GERD (46,70). Unfortunately, neither study used proton pump inhibitors or documented control of acid reflux by 24-hour esophageal pH testing. Also, one of these studies was published only in abstract form making critical evaluation difficult. Larrain et al. conducted a three-arm open-label prospective long-term randomized controlled trial of medical vs. surgical treatment of GERD in 81 nonallergic asthmatics (46). The minimum follow-up period was 6 months. Patients were randomized to placebo, cimetidine 300 mg four times a day, or the Hill antireflux surgical repair for GERD. Eighty-one patients completed this study, including 28 in the placebo group, 27 in the cimetidine group, and 26 in the surgery group. Baseline GERD symptoms were present in 60 of 81 (75%) patients, and the presence of GER was documented by either barium studies or pH testing. There was no description of the underlying asthma severity, medical therapy, or the comparability of asthma disease severity in each of the three groups. It is notable that 32 of the 81 patients had a history of cigarette smoking. Asthma symptoms improved in all three groups, with the greatest improvement occurring in the surgery (77%) and cimetidine groups (74%). It is noteworthy that the placebo group also had a 36% improvement in their mean asthma score. It is important to note that despite symptom improvement, there was no statistically

Design

Case series

Case series

Case series

Author, year (Ref.)

Sontag (67)

Perrin-Fayolle (68)

Tardif (69)

10

44

13

N

GERD symptoms in all No objective documentation GERD symptoms in all Positive pH test

GERD symptoms in all By pH test or endoscopy

Baseline GERD

Severe asthma 5/10 prednisone-dependent

Severe FEV1%: 68% No baseline inhaled steroids

11/13 daily BDs 7/13 steroiddependent

Baseline asthma

Table 5 Antireflux Surgery for Adults with Asthma and GERD

N/S

Nissen fundoplication

N/S

Type of surgery

18/44 had a 3-month trial of medical therapy N/S

N/S

Medical therapy

21 months

⬎5 yr

1–5 yr

Follow-up

GERD was cured in 8/10 Only 5/10 asthma improved, no cures Reduce prednisone 3/10

4/11 ⫽ stopped BDs 6/11 ⫽ reduced BDs by ⬎50% 2/7 weaned off steroids 3/13 died after surgery Cure: 1 (2.5%) Improvement: 18 (41%) No improvement: 15 (34%)

Comments

198 Kavuru and Richter

3-arm openlabel, prospective, randomized

Case series

Larrain, 1991 (46)

Johnson, 1996 (71)

118

Total: 81 Plac: 28 Cim: 27 Surg: 26

Total: 73 AA: 26 Ran: 24 Surg: 33

GERD in all

No description Hill antireflux of asthma sesurgical reverity in each pair group ? baseline RX 32/81 hx of smoking Respiratory Sx Fundoplication in 63/118 ? asthma in 14/63

By Ba⫹ or pH test GERD symptoms in 60/81

Nissen fundoplication

All groups were comparable No details on severity or baseline Rx

Positive pH test and esophagitis All had GERD symptoms No details

N/S

Cim 300 mg qid

GERD: Ran 150 mg tid ⬎ 1 yr.

3 yr

6 months

1–5 yr

Asthma improved or ‘‘cured’’ in 75% in surg group (c/w 9.1%, 4.3%) (? what criteria) D/C prednisone in 33% surg group (c/w 11%, 0%) Published only as an abstract Asthma symptoms improved in all 3 groups, with surg ⬎ CIM ⬎ placebo Placebo improved ⬎40% No significant objective improvement in FEV1 Relieved resp Sx 38/50 (76%) GERD improved in 43/50 (86%) Motility abnormality 17/50 (34%)

AA ⫽ antacid; Ran ⫽ ranitidine; Cim ⫽ cimetidine; BDs ⫽ bronchodilators; N/S ⫽ not specified; Ba⫹ ⫽ barium studies; Rx ⫽ therapy.

3-arm openlabel, prospective, randomized

Sontag, 1990 (70)

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significant improvement in objective measures of airflow obstruction including FEV1. This study did not capture ambulatory peak flow measures or peak flow variability. Sontag et al. performed a three-arm open-label, prospective, randomized, placebo-controlled study comparing ranitidine 150 mg three times a day, surgery with the Nissen fundoplication, and placebo in asthmatics with GERD (70). A total of 73 patients completed the study—26 in the control group (who used asneeded antacids), 24 in the ranitidine group, and 33 in the surgery group. All patients had symptoms of GERD with baseline documentation of reflux by pH testing and/or endoscopy. Details were not given regarding the severity of the GERD. There was no information given regarding the baseline asthma severity, the baseline medications required to control asthma, or whether the severity and type of asthma were accounted for and matched across the three groups. The total duration of follow-up was 1–5 years. The authors concluded that asthma improved or was cured in 75% of the patients in the surgery group, compared with 9.1% in the ranitidine group and 4.3% in the placebo group. However, details were not given as to how the improvement was defined. It was also noted that 33% of the patients in the surgery group were able to discontinue oral prednisone therapy compared with 11% in the ranitidine group and none in the placebo group. Due to the overall lack of detail in this abstract, it is difficult to make further conclusions about this study. Both the Larrain and Sontag studies are ambitious attempts to compare medical versus surgical therapies in a randomized fashion. However, they do not adequately answer the question, which subset of patients should undergo surgery for GERD in the setting of suboptimal asthma control.

V.

Proposed Approach to GERD-Associated Asthma

Our approach to GERD in asthmatics is summarized in Figure 2. We favor an aggressive empiric therapy for both GERD and asthma, with judicious use of diagnostic studies. For patients with suboptimal control of asthma, based on frequent symptoms, daily use of bronchodilators, need for prednisone bursts, and emergency visits, we carefully optimize conventional asthma therapy. Based on consensus guidelines, this would include patient education, trigger-avoidance measures, appropriate use of peak flow monitoring, and daily inhaled corticosteroids in appropriate doses. For patients who continue to have poor asthma control, a careful investigation is pursued to exclude asthma mimics and search for comorbid disease or exacerbating factors, including environmental allergies, chronic nasal and sinus disease (rhinitis, polyposis, sinusitis), pulmonary infiltrates, and gastroesophageal reflux. For patients who have symptomatic GERD and, perhaps, prominent nocturnal symptoms, we recommend specific lifestyle

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Figure 2 Proposed approach to GERD-associated asthma. For patients with suboptimal asthma control, optimize conventional asthma therapy according to guidelines including inhaled steroids. For persistent asthma, investigate comorbid disease and exclude asthma mimics. For GERD symptoms, trial of proton pump inhibitor for 12 weeks. If both asthma and GERD are improved, GERD is a significant factor that requires long-term management. See text for details. MDI: β-agonist metered dose inhaler; IC: inhaled corticosteroid; PPI: proton pump inhibitor; EGD: endoscopy; PEF: peak expiratory flow.

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changes and empiric therapy with proton pump inhibitors, 12-week trial at a dose of 20 mg bid for omeprazole or 30 mg bid with lansoprazole. We subsequently monitor both GERD and asthma by symptoms, peak flow diary, and rescue medication use. The outcome of this intervention could fall into one of four groups. Both GERD and asthma may be improved, which would suggest that GERD is an important trigger. In this subset, the next challenge is long-term management including gradual titration off proton pump inhibition to H2-RA and/or promotility drugs, long-term proton pump inhibitor therapy, or evaluation for surgery. GERD may be improved, but asthma may remain unchanged, suggesting that GERD is not an important trigger. If GERD is not improved with an empiric trial of proton pump inhibitor, further workup should include specific diagnostic studies such as pH testing with manometry and endoscopy to ensure that acid reflux has been adequately controlled.

VI. Future Directions Many questions remain regarding the relationship and proper therapy for GERDassociated asthma. Certainly, a large multi-institutional placebo-controlled study is needed to adequately address the efficacy of aggressive acid suppression in improving acid-related asthma symptoms. We would suggest a very high dose of proton pump inhibitor (omeprazole 40 mg bid or lansoprazole 60 mg bid) to best assure control of acid reflux, short of individual pH titration (an impossible task in a large study). The duration of the study should be at least 3–4 months, though others would argue one year since asthma exacerbation may have seasonal variations. Additionally, the therapy for asthma should be clearly defined and should include therapy as outlined by the consensus guidelines. The group to study is problematic, since many asthmatics may be ‘‘silent’’ refluxers. Therefore, a large study of all difficult to treat asthmatics, regardless of reflux symptoms, may best address the practical issue of whom to treat. By including detailed demographic analysis as well as comprehensive pulmonary and reflux evaluations (endoscopy, manometry, 24-hour pH test) and not stratifying for the symptomatic or physiologic presence of abnormal GERD, a study with adequate sample size (probably 150–200 patients per group) could help to validate or refine suggested predictors for a therapeutic response to acid suppression. If predictors are not identified but asthmatics do well with aggressive acid suppression, then an empiric trial will be the best diagnostic and therapeutic approach to these patients. If acid reflux can be defined as a common trigger for asthma, later studies can address the role of less aggressive therapy for GERD using H2-RAs and promotility agents. Finally, cost analysis and quality-of-life studies will be necessary to assess the cost trade-offs (i.e., expensive antireflux medications vs. possibly less

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antiasthma medications) improvement in quality of life, and health care utilization in these patients. We hope this review has clarified some of the problems with current medical studies assessing the treatment of GERD-associated asthma. Future directions and studies are outlined that should help to resolve this issue over the next 10 years, improving the care of our patients with asthma.

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Kavuru and Richter Irwin RS, Curley FJ, French CL. Difficult-to-control asthma. Chest 1993; 103:1662– 1669. Kamada AK, Szefler SJ, Martin RJ, Boushey HA, Chinchilli VM, Drazen JM, Fish JE, Israel E, Lazarus SC, Lemanske RF. Issues in the use of inhaled glucocorticoids. Am J Respir Crit Care Med 1996; 153:1739–1748. DeVault KR, Castell DO. Guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Arch Intern Med 1995; 155:2165–2173. Pope CE. Acid-reflux disorders. N Engl J Med 1994; 331:654–660. Simpson WG. Gastroesophageal reflux disease and asthma. Arch Intern Med 1995; 155:798–804. Howden CW, Castell DO, Cohen S, Freston JW, Orlando RC, Robinson M. The rationale for continuous maintenance treatment of reflux disease. Arch Intern Med 1995; 155:1465–1471. Kitchin LI, Castell DO. Rationale and efficacy of conservative therapy for gastroesophageal reflux disease. Arch Intern Med 1991; 151:448–454. Hamilton JW, Boisen RJ, Yamamoto DT, Wagner JL. Sleeping on a wedge diminishes exposure of the esophagus to refluxed acid. Dig Dis Sci 1988; 33:518– 522. Johnson LF, DeMeester TR. Evaluation of elevation of the head of the bed, bethanechol, and antacid form tablets on gastroesophageal reflux. Dig Dis Sci 1981; 26: 673–680. Dennish GW, Castell DO. Inhibiting effect of smoking on the lower esophageal sphincter. N Engl J Med 1971; 284:1136–1137. Kahrilas PJ, Gupta RR. Mechanisms of acid reflux associated with cigarette smoking. Gut 1990; 31:4–10. Kadakia SC, Kikendall JW, Maydonovitch C, Johnson LF. Effect of cigarette smoking on gastroesophageal reflux measured by 24-hour ambulatory esophageal pH monitoring. Am J Gastroenterol 1995; 90:1785–1790. Waring JP, Eastwood TF, Austin JM, Sanowski RA. The immediate effects of cessation of cigarette smoking on gastroesophageal reflux. Am J Gastroenterol 1989; 9: 1076–1078. Holloway RH, Hongo M, Berger K, McCallum RW. Gastric distension: a mechanism for postprandial gastroesophageal reflux. Gastroenterology 1985; 89:779–784. Becker DJ, Sinclair J, Castell DO, Wu WC. A comparison of high and low fat meals on postprandial esophageal acid exposure. Am J Gastroenterol 1989; 84(7):782– 786. Vitale GC, Cheadle WG, Patel B, Sadek SA, Michel ME, Cuschieri A. The effect of alcohol on nocturnal gastroesophageal reflux. JAMA 1987; 258:2077–2079. Berquist WE, Rachelefsky GS, Kadden M. Effect of theophylline on gastroesophageal reflux in normal adults. J Allergy Clin Immunol 1981; 67:407–411. Hubert D, Gaudric M, Guerre J, Lockhart A, Marsac J. Effect of theophylline on gastroesophageal reflux in patients with asthma. J Allergy Clin Immunol 1988; 81: 1168–1174. Ruzkowski CJ, Sanowski RA, Austin J, Rohwedder JJ, Waring JP. The effects of inhaled albuterol and oral theophylline on gastroesophageal reflux disease and obstructive lung disease. Arch Intern Med 1992; 152:783–785.

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33. Schindlbeck NE, Heinrich C, Huber RM, Muller-Lissner SA. Effects of albuterol (salbutamol) on esophageal motility and gastroesophageal reflux in healthy volunteers. JAMA 1988; 260:3156–3158. 34. Michoud MC, Leduc T, Proulx F, Perreault S, DuSouich P, Duranceau A, Amyot R. Effect of salbutamol on gastroesophageal reflux in healthy volunteers and patients with asthma. J Allergy Clin Immunol 1991; 87:762–767. 35. Kjellen G, Tibbling L, Wranne B. Effect of conservative treatment of oesophageal dysfunction or bronchial asthma. Eur J Respir Dis 1981; 62:190–197. 36. Castell DO, Dalton CB, Becker D, Sinclair J, Castell JA. Alginic acid decreases postprandial upright gastroesophageal reflux. Dig Dis Sci 1992; 37:589–593. 37. Buts JP, Barudi C, Otte JB. Double-blind controlled study on the efficacy of sodium alginate (Gaviscon) in reducing gastroesophageal reflux assessed by 24 h continuous pH monitoring in infants and children. Eur J Pediatr 1987; 146:156–158. 38. Stanciu C, Bennett JR. Alginate-antacid in the reduction of gastro-oesophageal reflux esophagitis. Lancet 1974; 1:109–111. 39. Richter JE, Castell DO. Gastroesophageal reflux: pathogenesis, diagnosis, and therapy. Ann Intern Med 1982; 97:93–103. 40. DeVault KR, Castell DO. Current diagnosis and treatment of gastroesophageal reflux disease. Mayo Clin Proc 1994; 69:867–876. 41. Vigneri S, Termini R, Leandro G, Badalamenti S, Pantalena M, Savarino V, DiMario F, Bettaglia G, Mela GS, Pilotto A, Plebani M, Davi G. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med 1995; 333:1106–1110. 42. Magee LA, Inocencion G, Kamboj L, Rosetti F, Koren G. Safety of first trimester exposure to histamine H2 blockers. A prospective cohort study. Dig Dis Sci 1996; 4:1145–1149. 43. Goodall RJ, Earis JE, Cooper DN, Bernstein A. Relationship between asthma and gastro-oesophageal reflux. Thorax 1981; 36:116–121. 44. Nagel RA, Brown P, Perks WH, Wilson RS, Kerr GD. Ambulatory pH monitoring of gastro-oesophageal reflux in ‘‘morning dipper’’ asthmatics. Br Med J 1988; 297: 1371–1373. 45. Ekstrom T, Lindgren BR, Tibbling L. Effects of ranitidine treatment on patients with asthma and a history of gastro-oesophageal reflux: a double blind cross over study. Thorax 1989; 44:19–23. 46. Larrain A, Carrasco E, Galleguillos F, Sepulveda R, Pope CE 2d. Medical and surgical treatment of nonallergic asthma associated with gastroesophageal reflux. Chest 1991; 99:1330–1335. 47. Harper PC, Bergren A, Kaye MD. Anti-reflux treatment in asthma: improvement in patients with associated gastroesophageal reflux. Arch Intern Med 1987; 147:56–60. 48. Blum AL, Adami B, Bouzo MH, Brandstatter G, Fumagalli J, Galmiche JP, Hebbeln H, Hentschel E, Huttemann W, Schutz E, et al. Effect of cisapride on relapse of esophagitis. A multinational, placebo-controlled trial in patients healed with an antisecretory drug. The Italian Eurocis Trialists. Dig Dis Sci 1993; 38:551–560. 49. Bailey B, Addis A, Lee A, et al. Cisapride use during human pregnancy. A prospective, controlled multicenter study. Dig Dis Sci 1997; 42:1248–1252. 50. Vandenplas Y, deRoy C, Sacre L. Cisapride decreases prolonged episodes of reflux in infants. J Pediatr Gastroenterol Nutr 1991; 12:44–47.

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67. Sontag S, O’Connell S, Greenlee H, Schnell T, Chintam R, Nemchausky B, Chejfec G, Van Drunen M, Wanner J. Is gastroesophageal reflux a factor in some asthmatics? Am J Gastroenterol 1987; 82:119–126. 68. Perrin-Fayolle M, Gormand F, Braillon G, Lombard-Platet R, Vignal J, Azzar D, Forichon J, Adeleine P. Long-term results of surgical treatment for gastroesophageal reflux in asthmatic patients. Chest 1989; 96:40–45. 69. Tardif C, Nouvet TG, Denis P, Tombelaine R, Pasquis P. Surgical treatment of gastroesophageal reflux in ten patients with severe asthma. Respiration 1989; 56:115– 116. 70. Sontag S, O’Connell S, Khandelwal S, Greenlee G, Chejfec B, Nemchausky T, Schnell T, Miller T, Brand L. Anti-reflux surgery in asthmatics with reflux (GER) improves pulmonary symptoms and function [abstract]. Gastroenterology 1990; 98: A128. 71. Johnson WE, Hagen JA, DeMeester TR, Kauer WKH, Ritter MP, Peters JH, Bremner CG. Outcome of respiratory symptoms after anti-reflux surgery on patients with gastroesophageal reflux disease. Arch Surg 1996; 131:489–492. 72. Peters JH, DeMeester TR. Gastroesophageal reflux. Surg Clin North Am 1993; 73: 1119–1143. 73. DeMeester TR, Bonavina L, Iascone C, Courtney JV, Skinner DB. Chronic respiratory symptoms and occult gastroesophageal reflux: a prospective clinical study and results of surgical therapy. Ann Surg 1990; 211:337–345. 74. Richter JE. Surgery for reflux disease—reflections of a gastroenterologist (editorial). N Engl J Med 1992; 326:825–827.

9 Surgical Treatment of Gastroesophageal Reflux Disease with Emphasis on Respiratory Symptoms

STEVEN R. DeMEESTER and TOM R. DeMEESTER University of Southern California School of Medicine Los Angeles, California

I. Introduction Gastroesophageal reflux disease (GERD) can be defined as an increased exposure of the esophageal body to refluxed gastric contents. The etiology of this increased exposure to gastric juice is largely biomechanical, and as a consequence it is uniquely suited to surgical therapy. The three main biomechanical causes for GERD are a defective lower esophageal sphincter (LES), ineffective esophageal clearance of refluxed material, and abnormalities of the gastric reservoir that augment physiologic reflux. Of these, a structurally defective LES is the most common cause of abnormal reflux. In 60–70% of patients with GERD, the LES can manometrically be demonstrated to be defective on the basis of one or a combination of three factors: an inadequate pressure, a short overall length, or a decreased length of esophagus exposed to the positive-pressure environment of the abdomen. Many of the remaining 30–40% of patients have early disease, and in these patients the LES is intermittently defective, usually during the postprandial period, due to gastric distension. Surgical therapy is ideal in patients with a defective LES since a fundoplication augments and restores competency to the LES and prevents intermittent unfolding of the sphincter during episodes of gastric distension. 209

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Inefficient clearance can result in abnormal esophageal exposure to refluxed gastric juice in individuals with normal LES and gastric function because of the failure to clear physiologic reflux episodes. Important factors in esophageal clearance include gravity, esophageal motor activity, salivation, and anchoring of the distal esophagus in the abdomen. Surgical correction of a hiatal hernia reanchors the esophagus in the abdomen and can improve esophageal clearance. Finally, gastric abnormalities that contribute to GERD include acid hypersecretion, gastric dilation such as can occur with chronic aerophagia or overeating, and delayed gastric emptying. In most patients a surgical antireflux procedure will improve gastric emptying. Thus, the combination of a fundoplication and repair of hiatal hernia in patients with GERD can improve or correct each of the three main factors responsible for abnormal gastroesophageal reflux. It is important to fully evaluate the potential causes for reflux prior to consideration of surgery, since each will influence the decision for surgery as well as the selection of an antireflux repair.

II. Considerations for Surgical Therapy In the pre–proton pump inhibitor era, the major indication for surgery was the failure of medical therapy to control a patient’s symptoms. However, symptoms of heartburn are now alleviated in nearly all patients by proton pump inhibitors, albeit frequently at very large doses. Pulmonary symptoms, on the other hand, are more difficult to treat medically. Richter reported that respiratory symptoms are improved in only about 75% of patients treated with 20 mg of omeprazole twice a day, and therapy is often required for 2–3 months before any change in symptoms is noted (1). It is important to remember that despite symptom control with pharmacologic therapy, the underlying defect remains uncorrected in these patients and reflux continues unabated. In patients with reflux-induced respiratory symptoms, pharmacologic therapy may decrease the quantity of gastric secretions and raise the pH of the refluxate. Nonetheless, reflux, pulmonary symptoms, and pulmonary injury may continue. Furthermore, any beneficial effects of pharmacologic therapy only occur if the medication is taken. Failure to take prescribed medication regularly and failure to follow the dietary and lifestyle modifications that help control reflux often causes prompt return or worsening of symptoms. On the other hand, an antireflux operation abolishes reflux and allows return to a normal diet and lifestyle, off all medication. Currently, surgical intervention is recommended for select subsets of patients with GERD, including those with risk factors for progressive or difficult-to-manage disease, those with advanced or complicated disease, those with drug dependency, and those with extraesophageal—in particular pulmonary—manifestations of reflux disease.

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A. Risk Factors for Progressive or Difficult-to-Manage GERD

Mechanically Defective LES

Careful follow-up of patients with GERD has allowed the identification of several risk factors, or markers, for patients with reflux disease who are likely to have progressive or difficult-to-manage disease. The first of these risk factors is the presence of a mechanically defective LES. An incompetent sphincter allows unrestricted reflux of gastric juice into the esophagus and overwhelms the normal clearance mechanisms. This leads to progressive esophageal injury and favors the development of complications of repetitive reflux including severe esophagitis, stricture, and Barrett’s metaplasia. The severity of these complications is directly related to the prevalence of a mechanically defective sphincter (2). There is a similar tendency in the occurrence of pulmonary complications. Sontag and colleagues studied the LES characteristics in patients with asthma. They reported that, compared to controls, asthmatics had significantly lower LES pressures, greater frequency of reflux episodes, and greater acid-exposure time. These findings were independent of bronchodilator medication (3). Composition of the Refluxate

The composition of the refluxed material is another risk factor for progressive disease. Patients who reflux both gastric and duodenal juice have been found to have a higher prevalence of esophagitis and Barrett’s esophagus than do patients who reflux gastric juice alone (4). Analysis of the composition of reflux in 100 patients with gastroesophageal reflux disease demonstrated that the patients with the greatest degree of mucosal injury (complicated Barrett’s esophagus) were more likely to have gastroduodenal as opposed to pure gastric reflux (Fig. 1) (5). Patients with Barrett’s have been shown to have both a significantly higher prevalence and duration of abnormal esophageal bilirubin exposure (a tag for duodenal juice) compared with patients who have only esophagitis (4). Furthermore, among patients with Barrett’s, significantly greater esophageal bilirubin exposure has been demonstrated in those with complications of Barrett’s, including stricture and dysplasia (6). Evidence is accumulating that bile salts are the noxious component in refluxed duodenal juice and that their ability to cause cellular injury is pH dependent. For bile salts to injure mucosal cells, they must be soluble and nonionized. At a pH of 7, greater than 90% of bile salts are in solution and completely ionized. However, at a pH between 2 and 7, a mixture of ionized salt and the lipophilic, nonionized acid is present. Acidification of bile to below pH 2 results in an irreversible bile acid precipitation. Thus, under normal physiologic gastric conditions, bile acids precipitate and are of minimal significance. In a more alkaline gastric environment, however, bile salts are partially dissociated and nonionized, and this nonpolar form is able to rapidly cross cell mem-

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Figure 1 Prevalence of gastric and gastroduodenal reflux in patients with either no mucosal injury, esophagitis, Barrett’s esophagus, or complicated Barrett’s esophagus.

branes and accumulate within mucosal cells where it is toxic to the mitochondria (Fig. 2). For bile acids to remain completely ionized and innocuous in a patient with reflux disease taking acid-suppression medication, the gastric pH must be maintained above 7 for 24 hours a day, 7 days a week for the patient’s lifetime. Not only is this impractical, but it is likely impossible unless very high doses of medication are used. The use of lesser doses may allow esophageal mucosal damage to occur while the patient remains relatively asymptomatic (4).

Pattern of Reflux and Extent of Esophagitis

Studies of numerous patients with reflux disease have demonstrated that those patients with supine and bipositional reflux, as opposed to upright reflux, tend to have more severe LES dysfunction and reflux disease (7). Current studies suggest that initially reflux occurs in the upright position during the postprandial period. Repetitive injury of the mucosa within the sphincter leads to the loss of sphincter function and supine reflux occurs. Esophageal body function initially compensates for reflux episodes occurring during the upright and awake periods by rapidly clearing the refluxed material. However, with bipositional reflux, esophageal body function begins to fail and severe esophagitis ensues (Fig. 3). Consequently, those patients found to have severe esophagitis at initial endoscopy are apt to be bipositional refluxers and to have a structurally defective sphincter

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Figure 2 Dissociation curve for bile acids. Only the soluble, nonionized form of bile acids are able to cross cell membranes, accumulate, and become toxic to the mitochondria. At pH ⬍ 2 essentially all the bile acids are in an insoluble, precipitated state, while at pH ⬎ 7 the bile acids are fully ionized. Thus, the conditions necessary to produce the injurious form of bile acids exist in the partially alkaline environment of the incompletely acid-suppressed stomach.

Figure 3 Postulated mechanism for the progression of reflux disease from disease confined to the lower esophageal sphincter to disease that has exploded into the esophagus.

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and poor esophageal clearance. They are thus at increased risk for progressive or difficult-to-manage disease and should be considered for surgical therapy. Genetic Factors

Males with reflux disease are more prone to develop Barrett’s metaplasia than are women, and young men have many years ahead in which to develop a complication of their reflux disease. In addition, patients with increased esophageal exposure to gastric juice and a family history of Barrett’s or esophageal adenocarcinoma may have a genetic predisposition toward the development of intestinal metaplasia, dysplasia, and cancer. B.

Advanced or Complicated GERD

A strong indication for surgical correction of reflux disease is the presence of advanced disease. This includes patients with complications of reflux such as stricture or Barrett’s metaplasia. Appropriate management of a reflux stricture requires control of the reflux with an antireflux procedure in combination with dilatation of the stricture. Similarly, the proper therapy for a patient with Barrett’s esophagus is an antireflux procedure. Evidence suggests that surgery reduces the risk for progression of metaplasia, formation of a Barrett’s ulcer, and the development of dysplasia or adenocarcinoma (8,9). C.

Drug-Dependent GERD

While proton pump inhibitors are extremely effective in healing esophagitis and relieving symptoms of reflux, they only work if they are taken. Hetzel et al. found that within 6 months of stopping proton pump inhibitor medication, ⬎80% of patients had recurrence of symptoms and esophagitis (10). Furthermore, patients who respond to a course of medical therapy but have recurrence of symptoms within 4 weeks after cessation of therapy are prone to drug dependency (2). This usually means life-long maintenance therapy with proton pump inhibitors, often with the need for dose escalation to stop breakthrough symptoms or persistent mucosal injury. Thus, a relative surgical indication is the patient who is drug dependent and unwilling to accept the inconvenience, expense, or side effects of life-long medication, as well as the dietary and lifestyle modifications imposed by their reflux disease. D.

Respiratory Manifestations of GERD

An increasingly more important group of patients who benefit from antireflux surgery are those with atypical and extraesophageal manifestations of reflux disease. These patients suffer from chest pain, chronic cough or throat clearing, wheezing, episodes of nocturnal choking and/or waking up with gastric contents

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in the mouth, apnic spells, hoarseness, laryngitis, or recurrent pneumonia. The end stage of repetitive pulmonary injury from reflux is bronchiectasis or pulmonary fibrosis. At the University of Southern California at least one patient has undergone bilateral lung transplantation for pulmonary fibrosis ultimately found to be secondary to chronic reflux and aspiration. Any patient with respiratory symptoms secondary to reflux should be considered for antireflux surgery, as these patients respond poorly to medical therapy compared to patients with heartburn symptoms. Despite the decrease in gastric acid secretion and neutralization of gastric pH with proton pump inhibitors, reflux, aspiration, and respiratory symptoms often persist. Respiratory symptoms can occur with overt as well as occult gastroesophageal reflux. In patients with overt symptoms of reflux, such as regurgitation and heartburn, it is typically not difficult to recognize that reflux may be a contributing factor to the respiratory problem. However, in patients who seek medical attention for respiratory symptoms with occult reflux, a high index of suspicion will be necessary to make the diagnosis. Even with direct questioning few of these patients have typical heartburn or regurgitation symptoms (Fig. 4). Compared to patients who present with symptoms of heartburn, endoscopic esophagitis appears to be less common in patients with laryngeal or respiratory symptoms (11). In patients with respiratory complaints consideration must be given to the possibility that gastroesophageal reflux is responsible, even in the absence of symptoms or endoscopic findings suggesting reflux. Evaluation of these patients requires 24-hour esophageal pH monitoring, often with two probes. Donnelly et

Figure 4 The incidence and severity of esophageal symptoms in 77 patients with chronic respiratory complaints resistant to medical therapy. Ultimately 54 of the 77 patients (70%) were demonstrated to have increased esophageal acid exposure on 24-hour pH monitoring.

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al. (12) as well as Jack and colleagues (13) have reported using simultaneous tracheal and esophageal pH monitoring to diagnose patients with respiratory symptoms caused by reflux. Tracheal pH should stay consistently above 6, and any dip below pH 6 is definitive evidence for reflux and aspiration. Katz monitored 10 nonsmoking patients who complained of hoarseness with dual pH probes (14). The proximal probe was placed 2 cm above the upper sphincter in the hypopharynx, and a drop to or below pH 4 in the proximal probe was found in 7 of the 10 patients. Three of these 7 patients had normal 24-hour acid exposure at the lower probe and would have been classified as not having reflux. Of importance, these patients were upright refluxers with high-frequency, short-duration reflux episodes. Dobhan and Castell, also using dual probes but with the upper probe located in the proximal esophagus, have shown that acid exposure below pH 4 occurs at the proximal probe in less than 1% of the total time and 0% of the supine time in normal volunteers (15). Subsequently, in a retrospective analysis of 54 patients with pulmonary symptoms suspected to be related to reflux who underwent 24-hour pH monitoring with dual probes, Schnatz and Castell found that 33% of patients had reflux only into the distal esophagus, 55% had a combination of distal and proximal reflux, and 12% had reflux only in the proximal esophagus (16). Without using a proximal pH probe, those patients with normal distal esophageal acid exposure but abnormal proximal exposure would have been missed. This study also pointed out the importance of documenting abnormal esophageal reflux in patients with respiratory symptoms prior to treatment. In the group of 54 patients, all with respiratory symptoms believed to be secondary to gastroesophageal reflux, 24-hour pH monitoring was normal in 22% of patients. While 71% of the patients with abnormal esophageal acid exposure documented on 24-hour pH monitoring reported an improvement in their respiratory symptoms with medical treatment, none of the patients with normal esophageal acid exposure on 24-hour pH monitoring had relief of respiratory symptoms with medical therapy. One must exercise caution, however, when excluding gastroesophageal reflux as a cause or contributing factor in patients with respiratory symptoms on the basis of one normal 24-hour pH monitoring study. Tracheal irritation and respiratory symptoms can persist for up to one week following a significant aspiration episode (17). Consequently, respiratory symptoms during a 24-hour pH test that do not correlate with a reflux episode do not exclude the possibility that intermittent episodes of reflux-induced aspiration are the cause. It is possible that intermittent aspiration episodes too infrequent to document on one 24-hour pH monitoring may produce chronic respiratory symptoms. On the other hand, just documenting abnormal esophageal acid exposure 5 cm above the lower esophageal sphincter on 24-hour pH monitoring in patients with respiratory symptoms alone is inadequate to conclude that reflux is the cause

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of the respiratory symptoms (18). It is important to correlate the timing of respiratory symptoms with a reflux episode, since we now know that while reflux can stimulate the onset of respiratory symptoms, it is also true that respiratory symptoms can precede and initiate an episode of reflux. Simultaneous ambulatory esophageal manometry and pH monitoring is one technique whereby the chronology and occurrence of reflux and respiratory symptoms can be evaluated, and the primary or secondary nature of the reflux determined (Fig. 5). This distinction is critical in evaluating patients with only respiratory symptoms for antireflux surgery, since patients whose reflux episodes are induced by respiratory symptoms such as cough or wheezing will not be helped by a fundoplication (18). Furthermore, treatment of the primary respiratory disorder in these patients often not only improves their respiratory symptoms, but also decreases reflux episodes (19). The best results following fundoplication have been in patients with respiratory symptoms that developed during or within 3 minutes after a reflux episode (18). Another important factor in patients with respiratory symptoms secondary to reflux is the function of the esophageal body. Studies have shown that in patients with reflux disease there is a direct correlation between the number of respiratory symptoms and the prevalence of a motility abnormality (Fig. 6). Overall, 45% of patients with reflux-induced respiratory disorders were found to have abnormalities in esophageal contractility or wave progression (18). The dysmotility in these patients interferes with the ability of the esophagus to clear refluxed acid, particularly in the supine position, and nonperistaltic contractions facilitate the propulsion of esophageal contents retrograde up into the pharynx. As a consequence of this intermittent aspiration of swallowed saliva and food, patients with motility disorders of the esophageal body tend to have respiratory symptoms that persist after antireflux surgery. Sontag and colleagues have speculated that aspiration of refluxed acid may initially sensitize the pulmonary tree to a variety of other stimuli and that as the process progresses, reflux and aspiration of acid become more obscure. Antireflux surgery at this stage may prevent acid-induced wheezing, but a hypersensitive pulmonary tree may still be prone to bronchospasm in response to other stimuli (20). Consequently, the results of ambulatory pH monitoring are not always predictive of which patients will symptomatically benefit most from antireflux surgery. Figure 7 is the algorithm we use to make a decision for surgery in a patient with respiratory symptoms secondary to occult gastroesophageal reflux. While there are few absolute requirements or contraindications for an antireflux operation, there are guidelines as to which patients with respiratory symptoms are most likely to receive the greatest benefit from surgery. In general, patients most likely to have a good outcome after a fundoplication will preoperatively demonstrate:

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1. Increased esophageal exposure to gastric juice on 24-hour esophageal pH monitoring of the distal esophagus 5 cm above the lower esophageal sphincter 2. Increased esophageal exposure to gastric juice on 24-hour pH monitoring of the proximal esophagus 1 cm below the cricopharyngeal sphincter 3. Respiratory symptoms that occur simultaneously with or within 3 minutes after an episode of reflux documented on 24-hour pH monitoring 4. A structurally or dynamically defective LES by manometry 5. Normal gastric emptying 6. Normal esophageal body motility 7. Improvement or relief of symptoms with acid-suppression medication III. Factors to Consider When Choosing the Proper Antireflux Procedure After selecting patients who likely would benefit from an antireflux procedure, the approach and type of fundoplication needs to be determined. The operation should be tailored to the patient’s physiology. Important factors to consider include esophageal length, esophageal body motility, the patient’s age and overall health, coexistent respiratory disease or pulmonary pathology, body mass index (obesity), and a history of previous upper abdominal or gastric surgery including a prior failed antireflux procedure. A. Esophageal Length

Perhaps the key initial determinant of the approach for an antireflux operation is the surgeon’s judgment of esophageal length. This is an all-important issue, because any repair that is done under tension is likely to fail. An absolute determinant of adequate length has not been identified; however, there are several clues to suggest the potential for esophageal shortening. The first clue is the finding

Figure 5 (A) The technique of simultaneous ambulatory esophageal manometry and pH monitoring allows objective documentation of reflux associated with respiratory symptoms. The abrupt increase in intrathoracic pressure that occurs with coughing is recorded by the intrathoracic pressure transducers and is easily recognized by the simultaneous nature and steep slope of the pressure recording. Coughing that occurs soon after the onset of a reflux episode may be the result of occult aspiration of refluxed gastric juice or a reflex brought on by esophageal acidification. (B) On the other hand, the increase in intra-abdominal pressure that occurs with coughing may overcome the antireflux mechanism and produce a reflux episode.

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of a sliding hiatal hernia that will not reduce radiographically in the upright position. A Type III, or combined sliding and paraesophageal hernia with a partial or complete intrathoracic stomach seldom reduces spontaneously, yet many of these patients have adequate esophageal length after intraoperative esophageal mobilization. Thus, nonreducibility of the hernia, like all clues, is not an absolute; rather, it is a warning sign to the surgeon that a short esophagus may be present. Similarly, the finding of more than 5 cm between the endoscopically identified gastroesophageal junction and the diaphragmatic crura suggests the potential for esophageal shortening. Lastly, both Barrett’s esophagus and esophageal strictures are commonly associated with shortening of the esophagus. When esophageal shortening is suspected, a transthoracic approach allows complete mobilization of the esophagus up to the level of the aortic arch. Careful division of vagal branches to the left and right pulmonary hilum and separation of the esophagus from the left mainstem bronchus are important aspects of esophageal mobilization and are best done transthoracically. With complete mobilization, often sufficient esophageal length is gained to allow an antireflux procedure to be accomplished without the addition of an esophageal lengthening procedure. In general, we have found that if the esophagogastric junction, marked intraoperatively with a stitch, can be reduced 2 cm below the crura, then a Nissen fundoplication can be performed with acceptable tension. Construction of a Belsey partial

Figure 6 Prevalence of abnormal esophageal motility defined as ⱖ20% abnormal esophageal contractions (simultaneous or dropped waves) in 54 patients with respiratory symptoms and increased esophageal acid exposure, stratified according to the number of reported respiratory complaints.

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Figure 7 Proposed management algorithm to select patients with unexplained recalcitrant respiratory symptoms for antireflux surgery.

fundoplication, on the other hand, requires 4 cm of intra-abdominal esophagus, and, consequently, more often requires the addition of an esophageal lengthening procedure. B. Esophageal Motility

Another critical factor to consider when choosing the proper antireflux operation is the status of the patient’s esophageal body. Poor esophageal motility not only influences the choice of antireflux procedure, but it has a direct bearing on the anticipated outcome of the surgery as well. Patients who demonstrate peristaltic contraction amplitudes of 20 mmHg or less in the distal three-fifths of the esophagus are considered to have poor motility, as are those with a named motility disorder such as scleroderma. These patients are at risk for postoperative dysphagia since the outflow resistance of the reconstructed cardia after a complete fundoplication may exceed the peristaltic power of the body of the esophagus. In patients with abnormal wave progression down the esophagus, such as those with nonspecific motility disorders consisting of ⬎10% dropped waves or ⬎20% segmental simultaneous contractions, a complete fundoplication is not

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associated with an increased incidence of postoperative dysphagia in our experience (21). In contrast, a patient with the manometric criteria of a named motility disorder characterized by a specific abnormal wave progression such as diffuse spasm is likely to continue to experience dysphagia after a fundoplication. For patients with reflux disease and documented poor motility, the preferred operation is a transthoracic partial fundoplication (Belsey Mark IV). A transabdominal laparoscopic option recently gaining favor is the Toupet procedure. An important observation is that esophageal shortening and poor motility often occur together, and a number of these patients will require both a gastroplasty to lengthen the esophagus and a partial fundoplication to prevent reflux (Fig. 8). C.

Factors Favoring a Transthoracic Approach

Relative indications for a transthoracic approach include obesity, prior upper abdominal operations including previous antireflux procedures, and the presence of pulmonary pathology in the left lung that requires operative evaluation or treatment. Traditionally, transthoracic antireflux operations are done through a left thoracotomy since exposure of the esophageal hiatus and diaphragmatic crura are limited from the right chest. An important indication for a transthoracic approach is evidence of a shortened esophagus by barium esophagram or endoscopy.

Figure 8 Prevalence of esophageal motor disorders in patients with and without short esophageal length.

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D. Factors Favoring a Transabdominal Approach

Clearly, laparoscopic antireflux surgery is associated with shorter hospital stays, improved postoperative comfort, and an earlier return to normal activities compared to an open abdominal or thoracic procedure. Any patient without a specific indication for a thoracic approach should be considered for a laparoscopic fundoplication. Prior abdominal operations not directed at the stomach or esophagus have not made laparoscopic fundoplication excessively difficult and do not represent a contraindication. Extensive adhesions may necessitate innovative or additional port placement. IV. Types of Antireflux Operations A. Complete Fundoplication

Antireflux operations are divided into those that create a complete, or 360° fundoplication and those that create a partial fundoplication. The complete fundoplication was devised by Rudolf Nissen in 1956, and in addition to being one of the easiest to teach and learn, it continues to be the most commonly performed and the most effective antireflux procedure. The Nissen fundoplication can be done as an open transabdominal, an open transthoracic, or a laparoscopic procedure. Worldwide experience with the open Nissen procedure has demonstrated that it is an effective and durable antireflux repair associated with minimal side effects, particularly when the modifications of a very short (1–2 cm) and loose fundoplication are incorporated. Our extensive experience with the Nissen procedure has convinced us of the importance of complete fundic mobilization with division of the short gastric vessels, routine crural closure, and the creation of a loose, short fundoplication under no tension. We secure the anterior and posterior fundus to each other and the esophagus using a single pledgeted mattress suture with a 60 Fr bougie in place to size the fundoplication. Numerous reports have found that greater than 90% of adults and children continue to have relief of their reflux symptoms 10 years after a Nissen fundoplication. Since the introduction of the laparoscopic Nissen fundoplication in 1991, many patients have benefited from the reduced hospital stay, less discomfort, and quicker return to work offered by the minimally invasive laparoscopic technique. Importantly, the technical details of performing the Nissen fundoplication are maintained in the laparoscopic approach, and thus similar excellent long-term relief of symptoms as has been demonstrated in the open procedure should be obtainable. Reports of individual and institutional experiences with several hundred laparoscopic Nissen fundoplications confirm excellent short-term results (22); however, 10-year follow-up of a large series of patients is not yet available. In patients with a shortened esophagus on preoperative evaluation, a transthoracic approach is currently recommended. After complete esophageal mobili-

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zation is accomplished, esophageal length can be assessed, and, if necessary, an esophageal lengthening procedure can be performed. If the G-E junction can be placed 2 cm below the crura, we have found that a Nissen fundoplication can be performed with acceptable tension. In our experience, the transthoracic Nissen is associated with the best long-term relief of symptoms and lowest rate of failure of any of the available antireflux procedures or approaches (23). B.

Partial Fundoplication

The oldest and most commonly performed partial fundoplication is the Belsey Mark IV fundoplication. Described in 1952 by Ronald Belsey, it represents the fourth and final variant of the procedure. It requires a transthoracic approach and consists of a 270° anterior fundoplication. It is a more difficult procedure than the Nissen fundoplication, and Dr. Belsey noted differences in the outcome when he versus others on his staff performed the operation. Nonetheless, long-term follow up is available on large numbers of patients, and the symptomatic recurrence rate after 10 years is 14.7% (24). It is important to recognize, though, that recurrence rates increase to 45% in patients with preoperative severe esophagitis and stricture. It is now recognized that this is due to the amount of esophageal shortening commonly associated with this degree of esophageal pathology. Consequently, a Collis gastroplasty should be added to the Belsey partial fundoplication in this setting. Horbach and colleagues assessed symptoms, esophagitis on endoscopy, and the results of 24-hour pH monitoring on a group of 37 patients before and after Belsey fundoplication (25). They reported that following operation 81% of patients had relief of their reflux symptoms and endoscopic resolution of esophagitis. Normalization of total reflux time was obtained in 73% of the 37 patients. These values are somewhat less than what is reported following a complete (Nissen) fundoplication and suggest that a partial fundoplication is not as effective a barrier to reflux as a complete fundoplication. The Toupet partial fundoplication, described in 1963 by Andre Toupet, was developed in an attempt to decrease the incidence of postoperative dysphagia and gas bloat symptoms that were seen frequently after a Nissen fundoplication at that time. The Toupet procedure and subsequent modifications consist of a posterior 180–270° partial fundoplication, as opposed to the anterior placement of the Belsey partial fundoplication. Originally done as an open transabdominal procedure, it is now also performed laparoscopically. While no long-term laparoscopic follow-up is available yet, the open Toupet procedure is reported to provide excellent relief of reflux symptoms in 90% of patients with up to 10 years of follow-up (26). In a series of laparoscopic Toupet procedures reported by Mosnier et al., early postoperative dysphagia was reported to be as high as 45%, but no patient continued to complain of dysphagia beyond 2 months (27). In our opinion, the major advantage of the Toupet procedure is that it offers a laparoscopic alter-

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native to the traditional transthoracic Belsey fundoplication for those patients with poor esophageal motility but no shortening. C. Gastropexy Procedures

The Hill repair was first introduced in 1967 by Lucius Hill as an alternative to the Nissen and Belsey fundoplications. It, like the other procedures, has undergone several modifications and refinements. As opposed to all other antireflux operations, the Hill procedure is not a fundoplication. Instead, it attempts to recreate a normal angle of entry of the esophagus into the stomach by anchoring the gastroesophageal junction in the abdomen at the level of the crural decussation just anterior to the aorta, and thereby reestablish normal geometry to the gastroesophageal junction. By suturing the gastroesophageal junction posteriorly to the preaortic fascia, the normal angle of His is reconstructed and the gastroesophageal reflux barrier is restored. An important adjunct to the operation is the use of intraoperative manometry to calibrate the repair. Using this technique, Low and Hill reported subjective good or excellent results in 88% of patients a mean of 17 years after the open Hill procedure (28). In 1994 Hill and colleagues described their early results with the laparoscopic Hill procedure in 40 patients (29). After a mean follow-up of 10 months, subjective good or excellent results were obtained in 92% of patients, and 24-hour pH monitoring showed no abnormal reflux in 91% of patients. In this series, nine patients with pulmonary symptoms including aspiration, asthma, pulmonary fibrosis, or chronic laryngitis underwent a laparoscopic Hill procedure. Improvement or resolution of symptoms occurred in six (67%). Early dysphagia was common, and 15% of patients required one or more postoperative dilatations. D. Esophageal Lengthening Procedure

In some patients, chronic inflammation has so shortened the body of the esophagus that despite complete intrathoracic mobilization there is insufficient length to allow construction of a tension-free fundoplication. The esophagus in these patients can be lengthened by means of a gastroplasty, described by J. Leigh Collis in 1961. This procedure creates 3–5 cm of neo-esophagus utilizing the lesser curve of the stomach around which a fundoplication is placed. The antireflux repair can then be placed below the diaphragm without tension. This segment of neo-esophagus, created from the lesser curve and gastrocardial junction, lacks peristalsis. We therefore favor a Belsey partial fundoplication in combination with the Collis gastroplasty, although others combine a Nissen fundoplication with Collis gastroplasty and report good results (30). Traditionally, creation of a Collis gastroplasty required a transthoracic approach; however, techniques have recently evolved for the construction of a transabdominal Collis gastroplasty utilizing a combination of stapling devices. Only

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limited experience with this approach is available, yet early results of this procedure in combination with a Nissen or Toupet fundoplication done via an open abdominal or laparoscopic technique have been encouraging. Given the inability to adequately mobilize the esophagus with an abdominal approach, it is probably best if the transabdominal Collis procedure is utilized only in those patients thought to have sufficient esophageal length preoperatively, but intraoperatively were found to have a shortened esophagus such that an antireflux procedure alone would be under excessive tension. V.

Surgical Complications

Important operative complications include gastroparesis from vagal nerve injury, dysphagia, recurrent reflux, chest pain from gastric ischemia caused by herniation of the repair into the chest, and the gas bloat syndrome. A.

Gastroparesis

Vagal nerve injury is usually well tolerated provided it is unilateral. Bilateral disruption is known to produce gastric stasis, and, if recognized at the time of the operation, a gastric drainage procedure should be added to the fundoplication. Typically, vagal nerve injury is not a significant problem at the first operation, but in redo fundoplications it can be very difficult to identify and preserve the vagi. B.

Dysphagia

Postoperative dysphagia is a significant source of concern for both the patient and the surgeon when it occurs. There are a number of factors to consider when analyzing this problem. Abnormal esophageal motility and dysphagia are both frequently associated with reflux disease. Our group reported a preoperative prevalence of dysphagia to some degree in 65% of 100 consecutive patients with reflux who underwent a Nissen fundoplication (21). Forty-four of the 100 patients had abnormal esophageal body motility. Postoperatively, with elimination of reflux and repair of any associated hiatal hernia, the prevalence and severity of dysphagia was markedly improved in these patients (Fig. 9). Mild dysphagia may be present for up to 3 months after an antireflux operation and is likely related to postoperative tissue edema. However, persistent postoperative dysphagia in a patient without dysphagia preoperatively implies a mechanical problem. Dysphagia induced by a fundoplication typically results either from not matching the fundoplication performed to the patient’s physiology, or from a technical failure in constructing the fundoplication. Patients with marked loss of esophageal function who have contraction amplitudes of less than 20 mmHg

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Figure 9 Prevalence and severity of dysphagia for all patients before and after Nissen fundoplication. Approximately half of the patients had moderate to severe dysphagia before operation. Both prevalence and severity markedly improved after Nissen fundoplication.

throughout the lower three-fifths of the esophageal body on preoperative manometry are at risk for dysphagia after a Nissen fundoplication. In this setting we prefer a partial fundoplication, since a complete fundoplication may prove to have too much outflow resistance for the severely impaired esophagus. Dysphagia can also be induced by an improperly constructed or herniated fundoplication. A Nissen fundoplication misplaced around the stomach (the so-called ‘‘slipped Nissen’’), or a fundoplication that is too long or too tight, or one that has herniated into the chest as a consequence of disruption of the hiatal closure can produce dysphagia. These are all technical mishaps that should be rare but are important to look for in evaluating the postfundoplication patient with persistent dysphagia. Table 1 reviews the reasons for a failed antireflux procedure in 65 patients who underwent a repeat operation. To minimize the occurrence of dysphagia related to a Nissen that is too long or tight, we recommend a very short (1 cm) fundoplication that is very loose or ‘‘floppy,’’ as it is performed over a 60 Fr bougie. Using these techniques, persistent or intermittent dysphagia of a degree that does not require bougienage has been reduced to 3% after Nissen fundoplication (31). Dysphagia requiring bougienage following the procedure is extremely rare. C. Recurrent Reflux

Recurrent reflux implies disruption of the fundoplication. Typically, excessive tension secondary to an unrecognized short esophagus is the major culprit for

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Table 1 Reasons for Failure of Prior Antireflux Procedure in 65 Patients Who Underwent Remedial Surgery Reasons for failure Placement of wrap around stomach Disrupted fundoplication Herniation of repair into chest Too long or too tight a wrap Operative damage to lower esophagus Primary motility disorder of the esophagus Ineffective but intact repair Total

No. of procedures (%) 22 (31) 17 (24) 12 (17) 5 (7) 4 (6) 5 (7) 5 (7) 70

both herniation of the repair into the chest and disruption of the fundoplication. In some patients with herniation of an intact fundoplication into the chest, no hiatal closure was performed as part of the antireflux repair. Several series have reported a high incidence of this complication without hiatal closure, and thus crural closure should be a standard part of an antireflux procedure in all patients. Previously, in patients with a short esophagus the antireflux repair was deliberately left within the chest. Patients in whom the repair herniated into the chest or was deliberately placed in the chest have a 20% incidence of gastric ischemia and perforation as a consequence of the inability to belch. This leads to intrathoracic distension of the stomach, as well as tissue ischemia caused by the compression and stretching of the gastric vessels as they pass through the hiatus. As a consequence, any repair left in the chest is in a precarious state and should be revised. D.

Gas Bloat Syndrome

Gas bloat syndrome refers to a condition whereby patients, typically after a complete fundoplication, feel bloated and are unable to belch and relieve gastric distension. We have found that mild gastric bloating is present in 11–23% of patients after antireflux surgery (31). However, this symptom has likely been overemphasized as a surgical complication, since others have found that the prevalence of bloating was similar in medically treated GERD patients. This complaint is probably related to the habit of excessive air swallowing learned by many patients with GERD in an attempt to clear the esophagus of refluxed acid. Most patients are unable to belch after a Nissen procedure and are likely to notice some mild bloating as well as increased flatus, but this tends to decrease with time as the habit of air swallowing is unlearned.

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E. Comparison of Complications in Open Versus Laparoscopic Antireflux Surgery

Laparoscopic antireflux surgery is well known to have an associated learning curve during which there is a higher incidence of complications including the need for conversion to an open procedure. This learning curve lasts for about 25 cases, after which laparoscopic antireflux surgery has an extremely low incidence of morbidity and mortality. Importantly, every effort is made to perform the fundoplication similarly to how it is performed in the open procedure. Thus, it is hoped that rate and nature of complications will be similar or less frequent than after an open procedure. Probably the most common complication, if it can be called that, of laparoscopic antireflux surgery is the need to convert to an open procedure. Often the need to open is based on poor visualization due to a large left lobe of the liver, adhesions, or obesity. Rarely is it related to bleeding or perforation of the esophagus, stomach, or bowel. Conversion rates in the published major series range from 0.5 to 14% but decrease to less than 1% in most centers as experience increases. Intraoperative splenic injury necessitating splenectomy in reported series of open procedures averages 2%, while it is 0% in several reported laparoscopic series. Likewise, mortality in open series is 0.5– 1% and is 0% in reported laparoscopic series. Wound complications are reported in 4% of open procedures and ⬍1% of laparoscopic procedures. One complication peculiar to laparoscopic surgery is gastric perforation related to traction with Babcock clamps; however, in most cases the perforation was repaired laparoscopically. The incidence of other complications, including atelectasis, pneumonia, urinary tract infection, and postoperative bleeding are quite similar between open and laparoscopic series of patients. Recurrence of reflux was noted in 3% of patients in one series of 100 open Nissen procedures followed for 10 years (31). Among 198 patients who underwent laparoscopic Nissen fundoplication, 92% of patients were free of reflux symptoms, 7% had mild symptoms, and 1% had moderate reflux symptoms a median of 12 months after the operation. In this series, the reoperation rate for failed Nissen fundoplication was 1.5% (22). VI. Results of Surgery Antireflux repairs are in general effective and durable. When surgically treated patients are compared to medically treated patients, they have better symptom relief and more consistent healing of esophagitis (32,33). The best studied repair is the Nissen, and several long-term follow-up studies suggest good to excellent results at 10 years in 90% of patients (Fig. 10). Partial fundoplications are not as durable. Ten-year follow-up on the Belsey Mark IV procedure suggests that symptomatically, 85% of patients have a good to excellent long-term result. Other partial repairs are less well studied, but likely will demonstrate outcomes similar

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Figure 10 Actuarial success rate of the Nissen fundoplication in the control of reflux symptoms. The numbers on the lower curve represent the patients at risk for each subsequent yearly interval from which the actuarial curve was calculated.

to the Belsey. Table 2 outlines our reported results in 82 consecutive antireflux procedures that were tailored to each patient’s preoperative esophageal function and length according to the algorithm shown in Figure 11 (23). Results with a Belsey partial fundoplication alone in our series are worse than when combined with a Collis gastroplasty. This perhaps indicates that patients with poor esophageal motility without shortening have intrinsic body dysfunction as opposed to dysfunction secondary to ongoing gastroesophageal reflux. An important consideration in the outcome of an antireflux procedure is that the success rate decreases incrementally with each attempt, and thus it is critical to do it right the first time (34). In patients with gastroesophageal reflux documented by a positive 24-hour pH monitoring test, a Nissen fundoplication will abolish reflux symptoms in 91% of patients over a 10-year period (31). Relief of respiratory symptoms after an antireflux procedure, while overall better than with medical therapy, is less reliable than relief of reflux symptoms. This is because improvement is dependent upon the status of the esophageal body and the presence of normal esophageal motility. Previously, we reviewed the outcome after antireflux surgery in 50 patients with classic symptoms of reflux disease who had, in addition, a significant respiratory complaint consisting of one or more of the following: cough, shortness of breath, choking, chronic throat clearing, pleuritic chest pain, wheezing, voice change, hiccups, or frank aspiration. Antireflux surgery resulted in the complete

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Table 2 Improvement in the Primary Symptom Responsible for Operation After the Various Tailored Antireflux Procedures

Abdominal Nissen Thoracic Nissen Belsey Collis-Belsey Total

N

No. of patients cured

No. of patients failed

% cured

49 20 6 10 85

44 19 4 8 75

5 1 2 2 10

90 95 67 80 89

Figure 11 Algorithm for selection of antireflux procedures on the basis of clinical and functional evaluation.

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alleviation or marked improvement of cough in 83%, choking in 86%, shortness of breath in 83%, throat clearing in 69%, voice change in 90%, wheezing in 64%, pleuritic chest pain in 100%, hiccups in 100%, and frank aspiration in 83%. Of the 12 patients with one or more symptoms that were not improved after surgery, nine of them (80%) had an esophageal body motor abnormality before surgery. Thirty-eight patients had normal preoperative esophageal motility, and respiratory symptoms were completely relieved after antireflux surgery in 29 of these patients (Fig. 12). Consequently, the improvement of respiratory symptoms in patients with overt gastroesophageal reflux disease treated surgically depends on two factors: whether a competent antireflux mechanism is reestablished and whether an esophageal body motor abnormality present before surgery persists after surgery (35). An even more complex group of patients are those with pure respiratory symptoms and occult reflux. Among 17 such patients we found that while 82% were improved by an antireflux operation, only 53% of patients had their symptoms completely relieved by surgery (18). Careful analysis of these patients demonstrates that the best results were obtained in the subgroup of patients with normal esophageal motility and respiratory symptoms that occurred during or within 3 minutes after a reflux episode or were unrelated to a reflux episode in a patient with increased esophageal acid exposure (Table 3). Antireflux surgery fails to improve patients who have respiratory symptoms that precede a reflux episode. In addition, surgery is unlikely to alleviate respiratory symptoms in patients with abnormal esophageal body motility regardless of the relationship of

Figure 12 The outcome of antireflux surgery on respiratory symptoms in patients with overt gastroesophageal reflux disease, stratified according to the presence of a motility abnormality.

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Table 3 Results of Antireflux Surgery a Success rate Relationship of symptoms to reflux episodes Related during or after an episode Related before an episode Unrelated to an episode Total

Normal motility

Abnormal motility

Total

2/2 0/2 5/5 7/9 (78%)

2/4 0/1 0/3 2/8 (25%)

4/6 0/3 5/8 9/17 (53%) b

a

In 17 patients with respiratory symptoms found to have increased esophageal acid exposure on 24hour pH monitoring using a single probe located 5 cm proximal to the upper border of the lower esophageal sphincter. Abnormal motility was considered present when there were ⬎20% simultaneous or repetitive contractions during a stationary motility study. b Fourteen (82%) of the patients had their symptoms improved by the operation, but for purposes of analysis only the nine patients who were completely free of symptoms after operation were considered successful.

the symptoms to reflux episodes. As a consequence of the abnormal esophageal body motility, these patients continue to aspirate esophageal contents postoperatively, and their respiratory symptoms persist. VII. Summary Respiratory symptoms can occur in conjunction with overt as well as occult gastroesophageal reflux. Patients with overt reflux seek medical attention for typical reflux symptoms like heartburn and regurgitation, and their respiratory complaints are secondary. Surgical fundoplication relieved the reflux symptoms in 86% of these patients, and in the majority of patients (76%) the respiratory symptoms were relieved as well. However, in patients whose respiratory symptoms are the primary reason for presentation to medical attention, occult reflux may be present and requires a high index of suspicion to diagnose. Frequently, neither typical reflux symptoms nor endoscopic esophagitis are present in these patients, and making the diagnosis requires 24-hour pH-monitoring techniques. The use of dual probes increases the likelihood of detecting abnormal reflux causing the respiratory symptoms since approximately 12% of patients with respiratory symptoms and abnormal esophageal acid exposure at an upper probe have normal acid exposure at the lower probe on 24-hour pH monitoring. Following antireflux surgery, 82% of these patients are improved, but respiratory symptoms were abolished only in those patients who had normal esophageal motility. Thus, the probability of relief of respiratory symptoms with an antireflux procedure is directly

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dependent upon the patient’s esophageal motor function. There is also a direct correlation between the number of respiratory symptoms a patient experiences and the presence of abnormal esophageal body motility. Therefore, efforts should be made to carefully assess the esophageal motility of patients with primary respiratory symptoms secondary to occult gastroesophageal reflux. Left untreated, repetitive aspiration can lead to progressive pulmonary dysfunction and ultimately bronchiectasis, pulmonary fibrosis, and death. References 1. 2. 3.

4.

5. 6.

7.

8.

9.

10.

11. 12.

Richter JE. Atypical manifestations of gastroesophageal reflux disease: pulmonary and ear, nose, and throat. Gastrointest Dis Today 1996; 5:1–7. Peters JH, DeMeester TR. Gastroesophageal reflux. Surg Clin North Am 1993; 73: 1119–1144. Sontag SJ, O’Connell S, Khandelwal S, Miller T, Nemchausky B, Schnell TG, Serlovsky R. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990; 99:613–620. Kauer WK, Peters JH, DeMeester TR, Ireland AP, Bremner CG, Hagen JA. Mixed reflux of gastric and duodenal juices is more harmful to the esophagus than gastric juice alone. Ann Surg 1995; 222:525–533. DeMeester SR. Management of Barrett’s esophagus free of dysplasia. Semin Thorac Cardiovasc Surg 1997; 9:279–284. Fein M, Ireland AP, Ritter MP, Peters JH, Hagen JA, Bremner CG, DeMeester TR. Duodenogastric reflux potentiates the injurious effects of gastroesophageal reflux. J Gastrointest Surg 1997; 1:27–33. Fein M, Ritter MP, DeMeester TR, Vos M, Hagen JA, Peters JH. Isolated upright gastroesophageal reflux is not a contraindication for antireflux surgery. Surgery 1997; 122:829–835. Ortiz A, Martinez de Haro LF, Parrilla P, Morales G, Molina J, Bermejo J, Liron R, Aguilar J. Conservative treatment versus antireflux surgery in Barrett’s oesophagus: long-term results of a prospective study. Br J Surg 1996; 83: 274–278. Sagar PM, Ackroyd R, Hosie KB, Patterson JE, Stoddard CJ, Kingsnorth AN. Regression and progression of Barrett’s oesophagus after antireflux surgery. Br J Surg 1995; 82:806–810. Hetzel DJ, Dent J, Reed WD, Narielvala FM, Mackinnon WD, McCarthy JH, Mitchell B, Beveridge BR, Laurence BH, Gibson GG, Grant AK, Shearman DJC, Whitehead R, Buclke PJ. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988; 95:903–912. Bremner RM, Bremner CG, DeMeester TR. Gastroesophageal reflux: the use of pH monitoring. Curr Probl Surg 1995; 22:434–558. Donnelly RJ, Berrisford RG, Jack CIA; Tran JA, Evans CC. Simultaneous tracheal and esophageal pH monitoring: investigating reflux-associated asthma. Ann Thoracic Surg 1993; 56:1029–1034.

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13. Jack CIA, Walshaw MJ, Tran J, Hind CRK, Evans CC. Twenty-four-hour tracheal pH monitoring-a simple and non-hazardous investigation. Respir Med 1994; 88: 441–444. 14. Katz PO. Ambulatory esophageal and hypopharyngeal pH monitoring in patients with hoarseness. Am J Gastroenterol 1990; 85:38–40. 15. Dobhan R, Castell DO. Normal and abnormal proximal esophageal acid exposure: results of ambulatory dual-probe pH monitoring. Am J Gastroenterol 1993; 88:25– 29. 16. Schnatz PF, Castell JA, Castell DO. Pulmonary symptoms associated with gastroesophageal reflux: use of ambulatory pH monitoring to diagnose and to direct therapy. Am J Gastroenterol 1996; 91:1715–1718. 17. Wynne JW, Ramphal R, Hood CI. Tracheal mucosal damage after aspiration. Am Rev Respir Dis 1981; 124:728–732. 18. DeMeester TR, Bonavina L, Iascone C, Courtney JV, Skinner DB. Chronic respiratory symptoms and occult gastroesophageal reflux. Ann Surg 1990; 211:337– 345. 19. Pellegrini CA, DeMeester TR, Johnson LF, Skinner DB. Gastroesophageal reflux and pulmonary aspiration: incidence, functional abnormality, and results of surgical therapy. Surgery 1979; 86:110–119. 20. Sontag SJ, O’Connell S, Khandeleval S. Antireflux surgery in asthmatics with reflux (GER) improves pulmonary symptoms and function. Dysphagia 1991; 6:62– 63. 21. Bremner RM, DeMeester TR, Crookes PF, Costantini M, Hoeft SF, Peters JH, Hagen JA. The effect of symptoms and nonspecific motility abnormalities on outcomes of surgical therapy for gastroesophageal reflux disease. J Thorac Cardiovasc Surg 1994; 107:1244–1250. 22. Hinder RA, Filipi CJ, Wetscher G, Neary P, DeMeester TR, Perdikis G. Laparoscopic Nissen fundoplication is an effective treatment for gastroesophageal reflux disease. Ann Surg 1994; 220:472–483. 23. Kauer WKH, Peters JH, DeMeester TR, Heimbucher J, Ireland AP, Bremner CG. A tailored approach to antireflux surgery. J Thorac Cardiovasc Surg 1995; 10:141– 147. 24. Orringer MB, Skinner DB, Belsey R. Long-term results of the Mark IV operation for hiatal hernia and analyses of recurrences and their treatment. J Thorac Cardiovasc Surg 1972; 63:25–53. 25. Horbach JMLM, Masclee AAM, Lamers CBHW, Gooszen HG. Prospective evaluation of 24 hour ambulatory pH metry in Belsey Mark IV antireflux surgery. Gut 1994; 35:1529–1535. 26. Bensoussan AL, Yazbeck S, Carceller-Blanchard A. Results and complications of Toupet partial posterior wrap: 10 years experience. J Pediatr Surg 1994; 29:1215– 1217. 27. Mosnier H, Leport J, Aubert A, Kianmanesh R, Idrissi MSS, Guivarc’h M. A 270 degree laparoscopic posterior fundoplasty in the treatment of gastroesophageal reflux. J Am Coll Surg 1995; 81:220–224. 28. Low DE, Hill LD. Fifteen to 20-year results following the Hill anti-reflux operation. J Thorac Cardiovasc Surg 1989; 98:444–450.

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DeMeester and DeMeester Kraemer SJM, Aye R, Kozarek RA, Hill LD. Laparoscopic Hill repair. Gastrointest Endosc 1994; 40:155–159. Orringer MB, Sloan H. Combined Collis-Nissen reconstruction of the esophagogastric junction. Ann Thorac Surg 1978; 25:16–21. DeMeester TR, Bonavina L, Albertucci M. Nissen fundoplication for gastroesophageal reflux disease. Ann Surg 1986; 204:9–20. Spechler SJ, Department of Veteran Affairs Gastroesophageal Reflux Study Group. Comparison of medical and surgical therapy for complicated gastroesophageal reflux disease in veterans. N Engl J Med 1992; 326:786–792. Isolauri J, Luostarinen M, Viljakka M, Isolauri E, Keyrilainen O, Karvonen A. Longterm comparison of antireflux surgery versus conservative therapy for reflux esophagitis. Ann Surg 1997; 25:295–299. Law SKY, Hagen JA, Kauer WKH, DeMeester TR. Reoperation for failed antireflux procedures. In: Bremner CG, DeMeester TR, Peracchia A, eds. Modern Approach to Benign Esophageal Disease. St. Louis: Quality Medical Publishing, Inc., 1995: 183–190. DeMeester TR, Johnson WE. Outcome of respiratory symptoms after surgical treatment of swallowing disorders. Semin Respir Crit Care Med 1995; 16:514–519.

10 GERD and Airways Disease in Children and Adolescents

STEPHEN J. McGEADY Thomas Jefferson University Philadelphia, Pennsylvania

I. Introduction Investigators have recognized that some gastroesophageal reflux (GER) is a normal phenomenon in all individuals. When GER causes any symptomatic condition or histopathologic change, however, it is designated as gastroesophageal reflux disease (GERD) (1). This definition applies to children and adolescents as well as to adults. It is to those instances where GERD causes extraesophageal disease involving the respiratory tract that this chapter pertains. Technological advances have begun to elucidate the role of GERD in a variety of upper and lower respiratory diseases of childhood, and it seems likely that when more extensive data are available GERD will be shown to play a role in some of the most vexing and recalcitrant diseases of the pediatric airways. Clinicians may be able to prevent or control some cases of such diverse diseases as chronic asthma and recurrent otitis media by treatment of GERD. This chapter will review what is known of the role of GERD in these diseases as they pertain to the older child and the adolescent, as well as the contemporary methods of diagnosis and treatment of GERD in this age group. There are no available epidemiologic data on the prevalence of GERD in childhood and adolescence, but it is known that the prevalence of GER is greatly decreased from what is observed in the infant (2). There are 237

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factors in young children that might make them more vulnerable to GERD, but other features of their lives would seem to make them less severely affected. Among the protective features, it is found that children and adolescents are less apt to have the type of abdominal obesity that appears to aggravate GER in the adult. They are also less likely to smoke tobacco and to drink alcohol and strong caffeine-containing beverages, all of which are known to facilitate GER in the adult. Among factors that might aggravate GERD in the child are the anatomically shorter esophagus, which facilitates access of the refluxed material to the upper airway and surrounding structures. The longer sleep time of the child can also contribute to GERD in that upper esophageal sphincter pressure is decreased during sleep, permitting access of refluxed material to the pharynx (3), and it is known that refluxed material is cleared less efficiently during sleep (4). The volume of food intake per kilogram of body weight beginning in infancy is three times that of the adult, and this undoubtedly places stress on the mechanisms that protect against GER (5). While this ratio of food intake to body weight decreases throughout childhood, it may remain a factor in children. Added to these factors is the common custom of children to take a bedtime snack, which may include milk or ice cream. The child eating such a meal goes to bed with a full stomach, the high fat content of which may delay gastric emptying considerably. The result may be that the child develops symptoms similar to an adult with GER (6), with belching, water brash, and heartburn (7) or the GER may be silent.

II. Upper Airway Manifestation of GERD When a connection between GER and extraesophageal disease was first noted, it was from recognition of the effects of GERD on the lower airways of children, but GERD is known to cause upper airway disease as well. In the past decade, the ability of GERD to produce upper airway disease in younger patients has received more attention. Table 1 lists the upper airway conditions that have been reported to be caused or aggravated by GERD. Advances in the technology of pH probe monitoring have led to studies in children in which the pH of the esophagus and pharynx are monitored for acid reflux simultaneously. Although single electrode studies had found decreases in pharyngeal pH in children with upper airway diseases (8), it was the simultaneous monitoring of the esophagus and pharynx that showed convincingly that GER into the esophagus led to the pharyngeal acidity associated with upper airway diseases (9). An important observation from this study was that pharyngeal pH of less than 6 was indicative of significant acidity, whereas esophageal pH of less than 4 has been considered indicative of gastric acid reflux into the esophagus. The connection between gastroesophago-pharyngeal reflux and upper airway disease is a fertile area for inves-

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Table 1 Upper Respiratory Tract Disease A. Laryngeal disease 1. Structural—vocal cord ulcers and granulomas 2. Functional/inflammatory a. Laryngomalacia b. Laryngitis and hoarseness c. Croup/spasmotic croup d. Stridor B. Rhinitis and rhinopharyngitis C. Sinusitis D. Pharyngitis/dysphagia/throat clearing E. Globus pharyngeus F. Otalgia/recurrent otitis G. Subglottic and supraglottic stenosis H. Chronic cough

tigation, and it seems likely that in future studies this degree of reflux will be found to play a role in a number of diseases affecting the upper airway as well as upper digestive tract (10,11) (see Chap. 12). A. Laryngeal Disease and GERD

It has been shown that refluxed acid peptic material may access the larynx in some children. Investigators have reported that GERD may lead to both structural damage to the larynx as well as milder inflammatory changes that produce a variety of functional impairments. Structural Vocal Cord Ulcers and Granulomas

Both vocal cord ulcers and granulomas have been attributed to GERD in adult patients (12,13), and it seems likely that similar injury occurs in children. These lesions are particularly prone to occur in intubated patients where mucosal disruption from the endotracheal tube may be followed by recurrent exposure to refluxed gastric contents (14). Pediatric otolaryngologists consider it imperative to diagnose and treat GERD before undertaking surgical repair of laryngeal stenosis lest ongoing GERD cause further injury to the newly repaired larynx or delay decannulation (14–16) (see Chap. 4). Inflammatory and Functional Laryngeal Diseases

Laryngomalacia is a condition observed almost always in infancy initially, but it may persist until later in childhood (17). The cause of laryngomalacia is floppy

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and redundant tissues in the area above larynx. These tissues, particularly the aryepiglottic folds, prolapse into the glottis during inspiration, causing stridorous breathing. There are several reports that associate laryngomalacia with GER. In one report 80% of a group of 20 children with laryngomalacia were shown to have GER by barium swallow studies (18). A second study of children with laryngomalacia severe enough to require surgical excision of the aryepiglottic folds showed that 50% of these children had GER, as demonstrated by barium swallow and esophagoscopy (19). Both of these authors proposed that the GERD played a role in the genesis of laryngomalacia in their subjects, suggesting that there was direct contact between refluxed acid-peptic material and the supraglottic tissues. Laryngitis and hoarseness have often been reported in the adult literature associated with GERD (20,21). The physical finding of red inflamed vocal cords in a patient with demonstrated GER suggests acid-peptic reflux to be the cause of these changes. There is also evidence that GERD can cause hoarseness and laryngitis in children. In one case report, a child with GERD demonstrated by pH probe and esophageal biopsy had resolution of hoarseness when the reflux was treated medically (22). Other reports in pediatric subjects have described this association as well (23) and one group has recommended that reflux be considered in any case of hoarseness in a child in which the workup, including laryngoscopy, is otherwise negative (24). Recurrent croup and acute spasmotic croup are also suspected of being caused by GERD. Most croup observed in infants and very young children is viral in etiology. This disease follows the pattern of presenting with an upper respiratory infection, which evolves into croup-like symptoms over several days. Another group of children who fit the profile of acute spasmotic croup develop croup-like symptoms but show no evidence of viral infection. In some of this latter group GERD has been thought to play a causative role (25). Children with acute spasmotic croup develop the croup-like symptoms spontaneously, tend to have frequent recurrences of these symptoms, and are sometimes suspected of being allergic. In several reports, evaluation of children with recurrent croup has revealed that a high percentage of these patients have GER. A study that evaluated reflux by several different modalities documented GER in 47% of 32 children with recurrent croup (26). Another study found no evidence of GER or pharyngeal reflux in the normal control subjects, but found both in each of the eight children who had two or more hospitalizations for croup (9). Laryngospasm and stridor are considered together since laryngospasm may lead to stridor. Complete laryngospasm produces total occlusion of the airway, but lesser degrees produce a variably narrowed glottis, and stridor may result (27). Stridor is unlike hoarseness as the latter occurs only during speech (22), while stridor, in contrast, consists of the ‘‘crowing’’ respirations that are particularly noticeable on inspiration. It has been shown that stridor can be provoked

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by GERD in some children (28). Mechanisms by which this could occur are either laryngospasm due to vagal reflexes from acid injury to an inflamed esophagus or direct acid injury to upper airway structures. It has been shown that acid applied to the esophagus in some subjects can elicit stridorous breathing (29,30), and studies in experimental animals suggest that reflexes are an important cause of laryngospasm (31). Other reports indicating that gastric acid can reach the pharynx suggest that direct acid-peptic injury to the larynx and surrounding structures might also cause stridor from glottic narrowing (9). An underlying anatomic abnormality may be a cofactor in the development of stridor. Treatment of GERD can, in some instances, lead to elimination of stridor, thereby establishing this connection quite clearly (28,30). Stridor and laryngospasm associated with GER are observed most often in infancy, but may persist until later in childhood. Neurologically impaired children are especially prone to these problems, and GERD should always be considered when such children develop stridor. B. Chronic Rhinitis and Rhinopharyngitis

Chronic rhinitis and rhinopharyngitis constitute a relatively unexplored complication of GER. In considering the high prevalence of these symptoms in the general pediatric population, it would be very useful to know the frequency with which they are caused by GERD. That GERD can be the cause of chronic rhinopharyngitis is shown by studies reported recently. Using a nasopharyngeal pH probe, investigators have shown that in 10 children with chronic rhinopharyngitis there was a significantly increased prevalence of low pharyngeal pH compared with 18 control subjects. These authors suggested that reflux of gastric contents into the nasal cavity was responsible for the inflammation observed (18). Less is known about the association of GERD and chronic sinusitis. It seems likely, however, that if gastric contents gain access to the nasal cavity, significant inflammation of the osteomeatal complex might ensue, leading to impaired mucus clearance from the sinuses and resulting disease. Further studies on this association will be of considerable interest. C. Otitis Media and Otalgia

Otalgia is a common pediatric problem and is most often associated with recurrent otitis media. In some cases, however, there is otalgia without otitis media, and this has been associated with GER in infants, children, and adults (32). The mechanism of this symptom is thought to be that of referred pain resulting from inflammation of the pharynx due to the refluxed acid-peptic gastric contents (33,34). The physical findings in these patients include a normal ear examination and variable degrees of erythema in the pharynx. Treatment of the GERD has been reported to lead to resolution of the otalgia (35). Recurrent otitis media has also been reported to result from GERD (8). Otitis is thought to be caused by

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refluxed material gaining access to the eustachian tube, which in some young children is unusually patulous and straighter than it is in the older child or adult (36). Awareness of the possibility that GERD can contribute to recurrent otitis media in some cases should lead to consideration of this preventable cause in evaluating children with recurrent otitis. D.

Pharyngitis and Chronic Throat Clearing

The complaint of persistent sore throat or chronic pharyngitis is sometimes heard in children. If cultures prove negative and physical findings suggest inflammation of the pharynx, as evidenced by erythema of the pharynx, uvula, and tonsils, consideration should be given to GERD as a cause (33,34). These patients often have worse throat pain in the morning upon awakening, since GER may be more damaging during sleep (4). Chronic throat clearing in children may suggest the presence of airway disease including allergic diseases and sinusitis. If these conditions can be ruled out, however, by history, physical finding, and the appropriate laboratory studies, GERD should be considered as a possible cause. A case report of a 15-year-old boy with ‘‘heavy drainage’’ in the throat during exercise found GER to be the cause. Treatment of the GER resulted in complete resolution of the patient’s symptoms (33). E.

Globus Pharyngeus

This is the sensation of having a lump in the throat. This same symptom, formerly referred to as ‘‘globus hystericus,’’ has been attributed to a psychoneurosis. However, it has been shown that GERD causing reflux pharyngitis may produce the symptom as well (37). Cases of globus pharyngeus due to GERD have been reported in adults, but they can occur in younger individuals as well. Awareness of GERD as a possible cause of this symptom will prevent the clinician from attributing it to psychological causes when a treatable physical problem is the true etiology (38). F. Subglottic and Supraglottic Stenosis

Subglottic stenosis has been reported in children with GERD. The role of GERD in causing subglottic stenosis is complex, particularly since many children developing this problem have a history of prolonged endotracheal intubation, which is known to cause the condition. In some children with this complication, however, GER can be shown to be present and is thought to play a role in causing stenosis (39). It is thought that the initial subglottic injury is from the endotracheal tube and that variable degrees of aspiration of refluxed gastric contents may serve as a cofactor in producing the subglottic insult ultimately leading to stenosis (1,40). It is known that endotracheal intubation disturbs the function of the upper

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esophageal sphincter so that the likelihood of GERD may be increased in the intubated child, and it has been found that pharyngeal reflux of gastric contents is common in supine intubated patients (1). It is also known from work in experimental animals that airway obstruction, which is often the indication for intubation, results in a powerful pressure gradient between the chest and the abdomen, which may lead to GER (14). Supraglottic stenosis/collapse is a condition identified in infants and children in which the supraglottic larynx is abnormally narrowed. In a recent report of 17 infants and children with this diagnosis, 53% were found to have a history of GER (41). As is the case for subglottic disease, the fact that an airway obstruction exists in supraglottic stenosis makes it difficult to know whether the reflux is a result of the airway obstruction or if the reflux may be causing or contributing to the supraglottic obstruction. H. Chronic Cough

The mechanism of chronic cough associated with GERD has been reviewed in Chapter 5. Chronic cough due to GERD has been documented in a large cohort of infants and children presenting with this symptom. Overall the investigators documented that GERD alone was the cause of cough in 15% of these subjects and appeared as an etiology most often in children aged 6–15 years (42). A similar study evaluating 88 older adolescents and adults found that among subjects with chronic cough who were nonsmokers and had a normal chest x-ray, GERD along with asthma and postnasal drip were the most common causes of the cough (43). Several authors have noted that coughing due to GERD in children is likely to present with nocturnal symptoms (44,45). Other authors have listed GERD as among the most common causes of chronic cough in the child and noted that the list of causes is remarkably similar in both children and adults (46). One study of subjects with chronic cough symptoms examined the interaction between coughing and episodes of GER using prolonged esophageal pH probe monitoring. Those investigators found that in some instances the GER and coughing were unrelated, in others the cough preceded the reflux episode, and in some the reflux could trigger coughing. It was suggested from this study that a vicious cycle of cough, reflux, and more coughing is seen in some subjects (47). Although not known to be caused by upper airway irritation, cough variant asthma is thought to be provoked in some patients by GERD. Cough variant asthma is seen primarily in children and consists of persistent coughing paroxysms in the absence of wheezing, with the cough having nocturnal predominance. The cough is relieved by bronchodilators (48,49). Cough variant asthma was the most common cause of chronic cough in the large study of infants and children described above (33) and is prominently listed by other authors in the differential diagnosis of chronic cough (46).

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McGeady III. GERD and Lower Respiratory Tract

Table 2 lists the diseases of the lower respiratory tract that have been associated with GERD. Most of these are relatively uncommon diseases or are seen primarily in special populations, such as neurologically impaired or developmentally delayed children. In contrast, asthma is quite common in the general population. The likely role of GERD in each is considered. A.

Aspiration Pneumonia

This condition occurs most often in children with some predisposing factor, such as neurologic injury or developmental delay (50–53). It is also described in otherwise neurologically normal children in association with depressed consciousness; aspiration during general anesthesia or CPR has been described (27,53,54). In both neurologically impaired and depressed patients, there is presumed to be dysfunction of the neural mechanisms that protect the upper airway when it is exposed to refluxed material. Developmentally delayed children may be prone to recurrent aspiration pneumonia (51,55), and these patients may develop some of the more serious complications. In addition to the neurologically impaired or depressed child, those who have had repair of esophageal atresia are at considerable risk for recurrent aspiration of refluxed material (56,57). These latter patients have abnormal motility of their esophagus, and the majority of them also have GER (27,57). Children with bronchopulmonary dysplasia (BPD) have likewise been identified as a high-risk group for GERD with aspiration. Since BPD often produces downward displacement of the diaphragm from air trapping, frequent coughing, and abdominal breathing due to airway obstruction, the condition is thought to favor occurrence of GER by overwhelming antireflux mechanisms (58). The tendency to aspiration of refluxed material in children with BPD may reflect neurological incoordination. The clinical signs of aspiration usually involve coughing and choking with food intake or during emesis.

Table 2 Lower Respiratory Tract Disease A. B. C. D. E. F. G. H.

Aspiration pneumonia Lung abscess Recurrent granulomatous pneumonia Bronchiectasis Chronic bronchitis Bronchiolitis obliterans Pulmonary fibrosis Bronchial asthma

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B. Lung Abscesses

These serious infections are believed to occur secondary to repeated aspiration of foreign material into the lungs (59). While material other than refluxed gastric contents may cause abscesses, the latter is known to do so often (60). Although mechanisms that have been reported to cause pulmonary abscesses include hematogenous spread of organisms and extensive bronchopneumonia, the possibility of repeated aspiration due to GERD should always be considered, especially in patients with developmental delay, depressed consciousness, or esophageal dysfunction, which, as noted above, favor aspiration pneumonias. Since lung abscesses are quite rare with foreign body aspiration, repeated episodes of aspiration may be needed to provoke this complication (59). C. Recurrent Granulomatous Pneumonia

This rare condition is manifested as a persistent infiltrate on x-ray and demonstrates diffuse granulomas on histologic examination of the lung. Recurrent aspiration of small quantities of regurgitated vegetable food materials has been found to be the cause. Evaluation of the lesions has implicated the cellulose fraction of the vegetable as opposed to the starch in the aspirated foods as the cause of the granulomas (61). As suggested with lung abscesses, individuals having any condition predisposing to recurrent aspiration should be considered to be at risk for developing granulomatous pneumonia. D. Bronchiectasis

This destructive pulmonary condition has been attributed to GERD resulting from the often severe and recurring pneumonias that occur with GERD and aspiration (62). Infection is the most common cause of bronchiectasis (14), and the persistent and recurrent nature of aspiration pneumonias in some children with GERD makes them vulnerable to such infections. The risk of developing bronchiectasis, which has a poor prognosis, is one of the principal reasons that GERD must be diagnosed and aggressively treated. E. Chronic/Recurrent Bronchitis

The persistence of signs and symptoms of tracheobronchitis beyond 3 weeks or their recurrence more than 4 times per year (the definition of chronic bronchitis) may occur as a result of GERD (27,53). When this syndrome occurs it reflects the continued exposure of the airways to the noxious effects of often small quantities of aspirated gastric contents (63). As with the other pulmonary complications of GERD, bronchitis represents one of the problems associated with reflux that should be treated aggressively, lest it lead to progressive structural lung damage.

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McGeady F. Bronchiolitis Obliterans

This condition represents a chronic persistent form of bronchiolitis that has been reported following a variety of insults to the lower airway (64). Prominent among these causes in children is GERD (65). Because of the chronic nature of bronchiolitis obliterans and its uncertain and at times poor prognosis, it is a pernicious complication of GERD with aspiration. Bronchiolitis obliterans is a problem that underscores the need to anticipate GER in the at-risk child and treat it aggressively when possible. G.

Pulmonary Fibrosis

This serious pulmonary disease has often been reported in adults in connection with gastroesophageal reflux (66). More recently the potential for the condition to occur in children with GERD has been recognized (27,53). The presumed mechanism for development of fibrosis is the repeated exposure of the lungs to small quantities of refluxed acid-peptic material. The resulting lesions are indistinguishable from those seen in idiopathic pulmonary fibrosis in the adult (66). H.

Bronchial Asthma and GERD

Of all the airway diseases in children and adolescents that may be due to GERD, asthma is by far the most prevalent, and thus arguably the most important. Recent epidemiologic estimates indicate that approximately 5% of children in the United States have bronchial asthma, and the prevalence appears to be increasing in recent years (67). The economic impact of this disease on American health care expenditures is very large, and there is evidence that a subpopulation of asthmatic patients with particularly severe disease account for a disproportionate share of these expenditures (68). If these negative trends are to be reversed, it is essential that all of the significant factors contributing to severe asthma be identified, and therefore it is particularly important that the contribution of GERD to severe bronchial asthma be defined. Unfortunately, despite a connection between GERD and asthma having been suggested over a century ago (69). The relationship remains unclear. The mechanisms by which GERD could adversely affect bronchial asthma are considered in detail in Chapter 7. The putative mechanisms usually cited in adults, microaspiration of refluxed acid-peptic materials, evocation of vagally mediated esophagobronchial reflexes, and increase in bronchial hyperreactivity secondary to esophageal acid exposure, are thought to be operative in children as well. It has also been suggested that a fourth mechanism might be an increase in IgE production. Denuding of the esophagus by acid reflux with enhanced allergen access to immunocompetent cells might lead to this outcome (66). Since most asthmatic children are atopic, this hypothesis may be worthy of consideration.

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Does Childhood Asthma Cause GER?

In childhood asthma, as in the adult disease, virtual universal agreement exists that there is an increased incidence of virtual gastroesophageal reflux (70–72). The pathophysiologic features of asthma that contribute to GER include coughing, which produces bursts of increased intra-abdominal pressure, abdominal breathing patterns contributing a sustained pressure increase, the powerful negative intrathoracic pressures during breathing with bronchospasm, and the downward displacement of the diaphragm during asthmatic episodes. These changes are similar in both adult and pediatric asthma.

Do Bronchodilator Medications Explain GER in Asthmatic Children?

A number of reports have made note of the fact that bronchodilator medications diminish the pressure of the lower esophageal sphincter (LES). Both β 2-agonists (73–75) and methylxanthines (76,77) have been reported to have this effect. In contrast, clinical studies that have evaluated the impact of these pharmacologic agents have usually not seen an increase in the number of episodes of GER in patients receiving them. In one very large study of adult asthmatics and nonasthmatic control subjects, it was found that compared to normal control subjects, asthmatics had considerably more GER. Among asthmatic subjects taking theophylline, β-agonists or both, however, there was no difference noted in LES pressure, the percent of time with decreased esophageal pH, or the number of GER episodes as compared to asthmatics taking none. The authors concluded that GER is a common feature of bronchial asthma rather than a medication side effect (78). Supporting the absence of a drug effect was a study of 16 children evaluated for GER during sleep. This report actually noted fewer episodes of GER in the 9 asthmatic subjects who had therapeutic serum theophylline levels than in the 7 control subjects who received no medications (79). Similar findings were reported in a study of 18 asthmatic children of whom 13 were receiving bronchodilators and 5 were not. The two groups had a similar prevalence of GER (80). Recent discoveries of how antireflux barriers normally work may reconcile the observations that bronchodilators decrease LES pressure but do not increase the occurrence of clinical GER. It has been found that reduction of LES pressure even to zero does not permit GER if the contraction of the crural diaphragm is preserved (81). Theophylline is known to enhance diaphragmatic contractibility (82,83) and may thereby actually inhibit GER even in the face of decreased LES pressure. Theophylline does, however, increase gastric acid secretion and thus may not be totally benign in the GERD prone asthmatic (84). Overall, there seems little reason to avoid most bronchodilators for fear of exacerbating GERD. However, theophylline dosage must be carefully titrated to balance its clinical benefits and side effects, and serum theophylline levels can be helpful.

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McGeady Does GERD Cause Childhood Asthma?

This is the crucial question to which there is as yet no final answer. Numerous studies have been carried out in adult asthmatics examining this question by attempting to recreate the conditions of GERD. The results have been conflicting. Table 3 shows data from five studies carried out in children and adolescents examining the question of whether recreating the conditions during GER, either by instillation of acid or by spontaneous GER, can result in asthma. The studies are small, most are uncontrolled, and diverse outcome measures of asthma are examined, with some reports relying on physical signs of bronchospasm. The two reports in this series that examine bronchial hyperreactivity (BHR) pursuant to esophageal acid exposure both found airway reactivity to be increased (80,87), a phenomenon that has also been suggested from studies in adults (88). There is a suggestion in several of these reports that reflux is most likely to cause nocturnal asthma (80,85,86), an observation that was made many years ago (89) and which may reflect both the more virulent nature of GER occurring during sleep (4) and the greater likelihood of asthmatics to develop bronchospastic episodes while asleep (90). Some reports of esophageal acid provocation including some of those listed in Table 3 and some performed in adult subjects, have failed to demonstrate any kind of airway response following provocation. Those studies, however, have not looked for increased BHR, so no comment can be made on that outcome measure (91,92). It would seem then that these ostensibly negative studies do not truly negate an effect of GERD on asthma. It is notable in Table 3 that acidprovocation studies in children and adolescents were all performed nearly a decade ago and that research in the importance of GERD in childhood and adolescent asthma has moved in a different direction. There are two principal reasons for the shift in focus of inquiry. The first reason is recognition of the fact that the interaction between asthma and GERD is quite complex. It has been noted, for example, that GERD does not cause bronchospasm or BHR in all asthmatics; it appears to do so only in those with preexisting esophagitis (85,93). In addition to this observation, GERD may not cause bronchospasm whenever it occurs, but may only do so at certain times of the day or night (85,94). Alternatively, it has been proposed that laryngeal exposure to irritant material is the stimulus most likely to elicit bronchospasm (95). To add complexity, none of the proposed mechanisms by which GERD might cause or aggravate asthma need exclude the others, and different ones may be operative in different patients or at various times in the same patient. One investigator has concluded that ‘‘it is very difficult to document a diagnosis of reflux-induced asthma. The only way to establish a causal relation is to demonstrate that the control of acid reflux by medical or surgical means ameliorates asthma’’ (96). The second reason for seeking an alternative investigative approach relates to the limitation of currently available technology. It has been stated that there is no acceptable diagnostic method available

18/0

9/7

9/0

25/0

15/0

Wilson (80)

Hughes (79)

Davis (85)

Martin (86)

deBlic (87)

Ref.

Subject/ Control

Intraesophageal acid instillation Spontaneous GER

Spontaneous GER during sleep

Intraesophageal acid installation

Spontaneous GER during sleep

Spontaneous GER in sleep Ingest HCl 0.001 N & 0.01 N

Method of provocation

Tidal volume O 2 sat Physical status

Histamine PC20 PEFR

Pulmonary parameter measured

No significant changes observed

No change

% Change observed in PFT

Not evaluated

↓ Histamine PC20

Evidence of BHR

0%

11/18

% of subjects reacting to provocation

Not stated

S Raw Carbachol PC20

No change S Raw

↓ Carbachol PC20

Not stated

Inductance 75% change in Not evaluated 4/9 (all with plethysmography mean inspira⫹Bernstein) Physical status tory flow. 40% ↓ inspiratory time seen only at 4 a.m. Barium swallow Physical status as- N.A. Not evaluated 3/16 wheezed pH probe sessment with GER episodes

Tuttle test Bernstein test pH probe

pH probe

N.A.

pH probe

Method of documenting GER

Table 3 Studies of Esophageal Provocation in Children

Cause and effect between GER and wheezing suggested in 3/8 patients with nocturnal asthma Spontaneous GER appeared to aggravate asthma by ↑ bronchial hyperreactivity

↓ PC20 at 90 min post–acid ingestion. No significant change in PEFR. If subject had GER and response to acid ingestion nocturnal asthma likely to be ↑ by GER. Patients with chronic asthma do not have ↑ GER at night. Reflux plays little if any role in nocturnal asthma. Patients with ⫹Bernstein may be highly susceptible to nocturnal wheezing from GERD

Authors’ conclusion

GERD in Children and Adolescents 249

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to confirm the presence of GERD-induced asthma (97). Treatment outcome studies of sufficient size to resolve the questions of whether GERD can cause asthma do not exist. To adequately address this issue, studies will have to be large enough to ensure sufficient statistical power to detect modest differences. Prior to examining any asthma treatment outcomes, there should be adequate control of GERD for a sufficient duration to allow healing of esophagitis. These proposed studies should not rely solely on improvement in pulmonary functions as a treatment outcome, since these improvements are known to occur slowly (98). Failure to demonstrate adequate suppression of GERD with usual doses of proton pump inhibitors has recently been demonstrated (99). Documentation of adequate acid suppression will clearly be needed in future studies. We all eagerly await this future research. What Can We Conclude About Asthma and GERD?

While the final answer to this question is not available, the preponderance of evidence supports a role for GERD in the cause and/or perpetuation of asthma in the child or adolescent. The known occurrence of GERD in the majority of asthmatics, the occurrence of reflux esophagitis in many, the studies showing that esophageal acidification can elicit bronchospasm or BHR, and reports claiming improvement in asthma with medical or surgical treatment, all support a role for GERD in causing or perpetuating asthma. It is also notable that virtually all investigators who have examined the problem of GERD and asthma have concluded that there is a connection (1,96). While some investigators have held that a causative role of GERD in bronchial asthma is unproven, few would deny its existence. IV. Diagnosis of GERD The methods available for the diagnosis of GERD are considered in detail with their indications and shortcomings in Chapter 3. Considered here will be the applicability of these tests to the child and adolescent whose size and ability to cooperate with testing will differ from that of the adult patient. Evaluation of the child and adolescent for GERD is based on identifying the best tests to define the cause of a specific set of symptoms. Since there are a large number of testing methods available, the testing is best done with input from a pediatric gastroenterologist if one is available. A.

History

Obtaining a history suggestive of GERD in the child and the adolescent presents a challenge to the clinician. The symptoms of GERD in the infant are considered

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in the previous chapter; with rare exceptions the symptoms in the older child and adolescent are similar to those in the adult (6). That is to say, children will have substernal burning most often but may have dysphagia, regurgitation, water brash, and belching as well (7). Unfortunately, many of these symptoms are beyond the vocabulary of the younger child, and the clinician must inquire carefully and in simple terms when eliciting this history. Adolescents may present a special challenge since they often have a need to deny illness and an aversion to any medical or parental intervention into their lives. Several visits and a friendly, nonconfrontational interviewing technique with attention to the amount of overthe-counter antacids being taken may be needed to learn the extent of the GERDrelated symptoms in the teenager. Despite the clinician’s best efforts it is sometimes the physical sequelae involving either the upper or lower airway that first draw attention to the presence of GERD. B. Physical Examination

In most instances of GERD associated with respiratory disease there are few physical signs supporting a connection on ordinary examination. In cases of GERD involving reflux to the pharynx, there may be redness in the throat, but even this sign is not reliable. Since some physicians have become proficient in performing rhinopharyngoscopy as part of a specialty evaluation, they may find inflammation of the larynx or surrounding tissues from GERD. Rarely the physician may see the peculiar head-cocking behavior associated with severe GERD that has been called Sandifer’s syndrome (100). C. Diagnostic Testing

When making a choice of diagnostic tests in the child or adolescent, the clinician balances the need for specific information against the invasiveness of the test and the child’s ability to cooperate. Ideally, sedation and anesthesia are avoided, but practically, these may be necessary. D. Scintigraphy

This is the most physiologic method of all testing for GER in children. A dose of radioactive technetium 99 proportional to the child’s weight is administered in a feeding. As milk is used for the vehicle in younger children, it is sometimes called a ‘‘milk scan.’’ After variable periods of time (such as 1, 4, and 24 hours) the upper abdomen and chest are scanned for radioactivity. The presence of radioactivity in the esophagus would indicate GER, while presence in the lungs would reflect aspiration. Aspirated material can be detected by this method many hours after the event has occurred. Although some authors have proposed scinitscan as a sensitive detector of GER in children (101), others find this study is insensi-

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tive in detecting GER when compared to esophageal pH probe monitoring (102). One authority has suggested that the diagnostic capability of scintigraphy is underdeveloped at most institutions and that much better information could be gathered with further development (53). E.

Barium Swallow

This study is also well tolerated in children, and sedation is seldom necessary. It is usually done as part of an upper gastrointestinal series, and fluoroscopic examination of the swallowing process is carried out to rule out aspiration during deglutition. This study is an important part of any evaluation when GERD is suspected to be associated with airway disease, since it both demonstrates the swallowing process and rules out anatomic defects in the upper gastrointestinal tract (103,104). As a means of demonstrating reflux, however, the barium swallow is relatively insensitive(24,53,102). Occasionally, particularly if done with air contrast, barium studies will demonstrate mucosal changes of esophagitis, but the ability to do so is limited to the more florid cases of inflammation. F. Esophageal Manometry

This study of esophageal pressures is usually performed prior to surgery for fundoplication to exclude esophageal dysmotility which might affect the surgical result (53). Since there is no strong correlation between reflux and LES pressure, the information gained from this study is of limited value in the overall assessment of GER (105). G.

pH Probe

Often described as the ‘‘gold standard’’ for the demonstration of GER (106), this study is very effective in evaluating patients with suspected GERD. While children and adolescents dislike passage of the monitor electrode via the nose into the esophagus, a staff member who is skilled in working with children can accomplish this without sedating the child, and once in place the probe is well tolerated even for a 24-hour study. The primary value of esophageal pH monitoring is the quantitative data that is generated on reflux. One can detect reflux into the upper esophagus using two channel pH recorders and may be able to correlate respiratory or other symptoms with reflux episodes (107). The limitations of pH probe monitoring are that the technique will not reflect reflux of neutral or alkaline gastric contents such as those that occur after meals. This study also fails to detect esophageal disease, recording only reflux episodes, which are not necessarily correlated with disease. A logistical problem is that although esophageal pH monitoring is available in medical centers, it may not be in remote areas. Overall, pH monitoring provides important information in diagnosis of GERD, and, as

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noted above, modification of the technique to monitor pharyngeal pH has begun to yield useful insights into several previously unrecognized complications of GERD (8). H. Esophageal Biopsy

Biopsy provides the definitive diagnosis of esophagitis. This is a critical piece of information since quantitatively abnormal reflux can occur without injury to the esophagus in some instances (4). In children, methods have been established to perform suction biopsies of the esophagus without endoscopy from a suction capsule passed to the appropriate level of the esophagus. The level of biopsy is determined from standard regression equations (53,108), or manometrically. Large series have demonstrated the safety and effectiveness of this procedure (109). Biopsy may and should be obtained during endoscopy, and the procedure permits visual selection of the biopsy site as well as overall assessment of the status of the esophageal mucosa. While suction biopsy can be performed with the child fully awake, endoscopy requires the child to be under sedation. I. Bernstein Test and Tuttle Test

The Bernstein test involves the alternating infusion of acid and saline into the esophagus through a nasogastric tube, with pain or discomfort upon acid infusion considered a positive result. Most often the test is used to determine whether esophagitis is present, but for this it is less sensitive than esophageal biopsy (53). The Bernstein test is occasionally able to reproduce the respiratory symptoms suspected of resulting from GER, and in that situation it is diagnostic. The Tuttle test for acid reflux places a standard amount of acid in the stomach and monitors esophageal pH for an hour following the instillation to determine whether reflux has occurred. This test has largely been replaced by esophageal pH monitoring (110). J.

Ultrasonography

A new and promising method for diagnosis of GER is the use of ultrasound. The technique is not yet widely accepted for diagnosing GER, but it has the advantages of being noninvasive, not exposing to radiation, and not requiring sedation of the child being studied. A recent report described completion of the study in 209 of 220 infants and children in which it was attempted, indicating that most children can cooperate well enough to permit a valid study (111). The ultrasound can detect reflux episodes in children as well as anatomic conditions such as hiatus hernia that may predispose to GER (112). It has been reported that ultrasonography compares favorably to other methods used to diagnose GER in children, including barium swallow (113) and pH monitoring (114). The use of color-coded

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Doppler ultrasonography in children has recently been described as a method to detect very small amounts of gastroesophageal reflux (115). The authors claimed that the color-coded Doppler increased sensitivity of the method to 94% using comparison with 24-hour pH monitoring. Despite these impressive findings, the authors suggested use of the technique as a supplement to pH probe monitoring in evaluating children with suspected GER. Other investigators have described the use of endoscopic ultrasonography in which the ultrasound probe is passed into the esophagus. This technique has been said to be a method for staging the degree of severity of reflux esophagitis as well as its response to therapy (116). Overall, ultrasonography appears to have many advantages compared to some older technologies used to diagnose GER in children, although additional studies are needed to confirm the claims made and to compare it to more traditional tests. It seems likely that the technology of ultrasonography will improve in the future and that refinements will be made that will enhance the power of this test to diagnose GER and the attendant abnormalities. V.

Treatment of GERD

A detailed consideration of the available medical and surgical treatment of GERD is presented in Chapters 8 and 9. The discussion in this chapter will be limited to therapies for GERD in children and to the consideration of their special needs. In planning GERD therapy in children, it is important to view the child as a young person whose life can be expected to span seven or eight decades. This fact emphasizes the need to consider the likely duration of treatment for GERD and any attendant airway disease. Second, the developmental aspects of the child or adolescent need to be considered in devising a treatment plan. Since children are in their formative years, it is important that they be enabled, to the extent possible, to carry out the educational, athletic, and playtime activities that their peers do. Children unable to do so may develop a self-image of being sickly or inadequate. Finally, the cost of therapy of GERD in purely economic terms needs to be considered (117). Many families are devastated by the costs of a chronic illness in a child, and GERD is no exception. Unfortunately, at this time there is still insufficient information to respond to all of the considerations delineated above and to recommend optimal therapy for each child. The available information must be synthesized, and future studies carefully designed, in order to define the treatment of choice for GERD in children and adolescents with airway disease associated with this condition. Some of what is known of GERD therapy is described below. A.

Conservative Management of GERD

While it is common for GERD in the infant to resolve spontaneously, there is evidence that as many as 50% of older children diagnosed with GERD will have

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persistent disease requiring chronic therapy (118,119). Simple, cost-effective measures for treatment of GERD include avoiding food intake for at least 3 hours before bedtime (107). As noted above, the bedtime snack is a common and pleasurable custom of many children in the United States. Adolescents, who may eat continually, seldom stop grazing as bedtime approaches. However, in the child or teenager with a diagnosis of GERD, this activity should be discouraged so that the stomach is relatively empty when the patient becomes recumbent. Tight clothing and obesity increases intra-abdominal pressure and thereby GER episodes, and these risks should be avoided. The sleeping position that best avoids reflux is not known with certainty, but some authors have suggested that sleeping prone is beneficial (6). Propping the head of the bed by about 6 inches has been recommended by some (2,6), however, a recent report did not find benefit in this practice (120). The avoidance of foods such as chocolate, peppermint, coffee, citrus, fats, and carbonated beverages (which cause bloating) has likewise been recommended as a means of controlling gastric acidity and LES tone (53,121). Cigarette smoke has been shown to adversely affect GER in smokers. Avoidance of secondhand smoke in the young child and avoidance of smoking or smoke exposure for the adolescent are well advised. Since respiratory diseases such as asthma, BPD, and cystic fibrosis are known to aggravate GER by the mechanisms described above, it may be difficult to successfully treat GER while the effects of the coexisting respiratory disease are at work. It is important then to employ all of the therapies available to bring these respiratory conditions under optimal control while treating the GERD. If a vicious cycle exists of a respiratory disease affecting GERD, which in turn aggravates the respiratory disease further, the cycle may need to be broken at several points. Despite all of these precautions being carried out, many children with GERD will continue to have symptoms, and for these patients pharmacologic therapy is indicated. B. Pharmacologic Treatment of GERD

A large number of drugs are used for treatment of GERD, and the pharmacology and relative efficacy of these agents are discussed in Chapter 8. The drugs used in children are used in adults, with the dosages made proportionate to the size of the child. In addition, there are some caveats on the long-term effects of some of these agents in children. Therapeutic agents used to treat GERD in children are divided into the three categories of acid reducing agents, prokinetic agents, and mucosal protecting agents. Acid-Reducing Agents

Acid-neutralizing agents are the historical mainstay of therapy to reduce gastric acidity. They are usually given as a liquid to the younger child but may be given as tablets to the older child or adolescent. Dosage guidelines are vague, but usu-

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ally 0.5–1.0 ml/kg/dose is prescribed three to eight times daily. Drawbacks include the unpalatability of the drugs, the side effects of diarrhea or constipation (53), and the need for frequent administration, which may be difficult in a schoolage child. Overdosing with these agents is possible and should be avoided. Alginic acid combined with an antacid is said to offer extra benefit, forming a viscous solution in the stomach that acts as a mechanical barrier to acid. Indications are that its effect is comparable to the antacids alone (121). H 2 blockers are used in children of all ages, although none are currently FDA approved for pediatric use. The number of these agents available in the United States is continually increasing, and there is no firm experimental evidence to recommend one compound over another on the basis of drug efficacy (122). There is a difference in recommended frequency of administration, however, and this feature may lead to greater compliance as well as less interference in the daily activities of school-aged or older children. Ranitidine (Zantac) and famotidine (Pepcid) are usually recommended to be given three times per day versus cimetidine (Tagamet), which is given four times per day. The author’s experience and that of others is that treatment failures, as judged by esophageal pH probe monitoring, are common with H 2 blockers. Follow-up studies while the patient is receiving the H 2 blocker to demonstrate suppression of gastric acid secretion are necessary even when maximum recommended doses are given (102). One report of ranitidine given as a single bedtime dose to a group of asthmatic children and adolescents described a 30% reduction in nocturnal asthma symptoms (123). The authors were unimpressed with this result, although it was statistically significant, and they stated that acid suppression had not been demonstrated in their study. They urged additional, better controlled studies of asthmatic subjects using these drugs. Apart from this report, however, there are no data by which to judge the efficacy of H 2 blockers in pediatric asthma associated with GERD. Proton pump inhibitors have been used in the United States for several years—initially, omeprazole (Prilosec) and, more recently, lansoprazole (Prevacid). These agents are recognized as being more effective acid suppressors than are H 2 blockers. Dosages of omeprazole ranging from 0.7 to 3.3 mg/kg/day were required to suppress gastric acidity in one study (124). This nearly fivefold range in dosage required to achieve acid suppression is reflected by observations in two studies of this drug in adults, where very high doses were needed in some subjects to achieve acid suppression (99,125). It appears that in treatment with omeprazole, as is true for the H 2 blockers, treatment failures are common. Verification of acid suppression in the individual patient is essential regardless of the dose administered. Pediatric studies have demonstrated elevated gastrin levels in children treated with omeprazole. The effect over the long term is unknown, but there is concern that the persistently elevated gastrin might lead to argyrophyll cell neoplasia (124). There are no data on treatment of pediatric airway disease

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with proton pump inhibitors, but preliminary reports of treatment of adult asthmatics with omeprazole are very encouraging (99,126). Experience with lansoprazole in children is limited and awaits further exploration. Prokinetic Agents

Prokinetic agents have been successfully used for treatment of GERD in some children. These agents are thought to increase LES pressure, improve esophageal clearance, and facilitate gastric emptying. Bethanecol was the first prokinetic agent used. It has not been shown to be consistently successful in treatment of reflux (127). There are also concerns that the use of bethanecol, which is a cholinergic agonist, might be aggravating in children with reactive airway disease. The drug is used infrequently in treating GER in children at present. Metoclopramide (Reglan) has been used for over a decade in the United States in the treatment of GER, but has not been identified as a drug of choice due to reports that question its efficacy (128,129). The side effect profile of metoclopramide includes CNS symptoms including irritability, extrapyramidal effects, and tardive dyskinesia. The author’s experience is that metoclopamide in usual doses, even when combined with an H 2 blocker, does not reliably abolish GER in asthmatic children (102). Cisapride (Propulsid) has been used in children with GER for several years in the United States. The drug appears to be effective and to have fewer undesired side effects than other prokinetic agents. Some authorities consider cisapride to be the prokinetic drug of first choice for GER in children and adolescents. Domperidone is an experimental prokinetic drug but is available in Europe. One study of 55 children with cough comparing cisapride and domperidone found domperidone to be superior in preventing GER by scintiscan, although differences were slight (130). Several studies have evaluated the effect of prokinetic agents in airway disease of children. The above-cited study comparing cisapride and domperidone involved children with chronic cough and showed that with either agent the cough cleared in approximately two thirds of patients (130). An uncontrolled report describing use of cisapride therapy for 3 months in 36 children with uncontrolled asthma revealed that there were highly significant improvements in both the clinical asthma scores and in the pharmacologic score of asthma medications (131). Some authors have described combination of prokinetic drugs with acid-reducing agents, either H 2 blockers or proton pump inhibitors being an effective antireflux regimen (109). These combinations, given in dosages sufficient to achieve suppression, may prove to be quite effective in treatment of GERD with airway disease. At present, however, every known acid-suppressive regimen requires a follow-up assessment by pH probe to ensure that suppression has actually been achieved (102).

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Mucosal-protecting agents consist only of sucralfate (carafate), although some have suggested that alginic acid (see above) behaves as a mucosal protector as well. Sucralfate has been reported to be an effective agent in treatment of reflux esophagitis in children (132). The agent is relatively nontoxic and is minimally absorbed from the gastrointestinal tract. C.

Surgery for GERD

The decision to undertake surgery in GERD with airway disease is made only after other remedies have failed or proved impractical. Considerations include the surgical risk involved, the impact of the procedure on the child, the cost, and the likelihood that the surgery will be beneficial for a prolonged period. Often considerations focus on the effectiveness of current therapy and the impact of the child’s GERD and its treatment on him or her and on the family. In considering the latter, relevant questions address days of school absenteeism, ability to play with friends or to play sports, and overall quality of life. If the decision to proceed with surgery is made, there are a number of procedures described. Recently the use of laparoscopic surgery has been introduced as a means to perform surgery with reduced risk, cost, and morbidity. Complete description of these surgical procedures is provided in Chapter 9. The surgical procedures that have been advocated for children balance the need to decrease reflux with that to preserve other functions of the upper gastrointestinal tract including swallowing, belching, or vomiting. The complications that have been observed postoperatively in children have been the result of the fundoplication either being too obstructing, not preventing GER, or breaking down over time with recurrence of GER. Experience in both adult and pediatric patients has emphasized the need to evaluate the total upper GI tract, including the status of the motility of esophagus and the ability of stomach to empty, before deciding which surgical repair to undertake (123,124). Common Surgical Repairs

Nissen fundoplication is the single most commonly used procedure in children today. The postoperative complications in children include gas bloat, dysphagia, and need for dilation (133). There is a small but significant failure rate of the fundoplication wrap following surgery, and it has been reported that failure in children is most often due to the stress placed on the wrap by persistent airway disease (134,135). It is necessary therefore to treat the airway disease vigorously postoperatively to minimize this problem. The long-term integrity of the wrap of gastric fundus around the esophagus seems to determine the success of the outcome in adults with Nissen repairs who have been followed longitudinally

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(136). This determinant applies to children as well. It is recognized that children with cystic fibrosis, asthma, BPD, and chronic pulmonary infections have an increased propensity for wrap disruption (137). Usually, a temporary gastrotomy tube is placed at time of surgery to decompress the stomach during early healing. Depending on preoperative findings, a pyloroplasty or gastric antroplasty may be indicated to facilitate stomach emptying (137). The Thal procedure is preferred in children in whom there is esophageal dysmotility, since it only wraps the fundus three fourths of the way around the esophagus and is said to permit the esophagus to empty more easily into the stomach. This procedure is often used in neurologically impaired children (137). Some experienced surgeons feel, however, that recurrence of GER is more common with the Thal procedure than with the Nissen fundoplication, and therefore it is less often used (137). The recurrence of GER following Nissen fundoplication has been reported as being between 0 and 12%, with a 12% recurrence rate being reported in one large series of 242 children followed for an average of 30 months (138). Data on comparable series following Thal procedure are not available. Other procedures include the Borema anterior gastropexy, the Hill posterior gastropexy, the Belsey Mark IV, and a number of other procedures. In general they are less often used then the Nissen and Thal procedures and may have a higher failure rate (136,137). In one other procedure a silastic elastomer prothesis in the form of a c-shaped ring, called the Angelchik prosthesis, is placed around the esophagogastric junction as an antireflux device. This device has been reported to work effectively in children, performing comparably to Nissen fundoplication (139). However, some authors have expressed concern that complications such as including migration of the prosthesis occur too often and urge more experience with the device before general adoption (133). Laparoscopic Nissen fundoplication has been used by pediatric surgeons for the past 6 years, and results in adults have been reported to be comparable to those with the open surgical procedures (140). The applicability to children remains to be more fully evaluated, but one experienced pediatric surgeon has recommended that, at this time, the procedure seems best suited for children with GER who are over 5 years of age and who are not neurologically impaired (137). The Role of Surgery

It has generally been held that most children and adolescents with GERD do not need surgery (6). Indications for surgical intervention have included the development of Barrett’s esophagus in which the squamous epithelium of the esophagus is replaced by columnar epithelium and strictures of the esophagus resulting from GERD. Intractable symptoms, including respiratory disease, caused by reflux are also accepted as an indication for surgery. Recent studies in adult patients have

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proposed that with use of laparoscopic fundoplication, surgery is preferable to long-term medical treatment of GERD (141,142). Insofar as GERD may be part of a vicious cycle in airway disease like asthma, it may be time to reconsider the role of surgery. When it is recognized that the asthmatic child may have the disease for many years or throughout his or her life span, the cost of GERD in personal as well as economic terms can be considerable. Sufficient data to define the indications and effectiveness of surgery for GERD in chronic diseases of the pediatric airways do not exist at present. The problem of severe childhood asthma is great enough, that carefully controlled, multicenter studies of patients matched for disease severity and randomized to receive medical or surgical treatment would be quite helpful. A report of adult asthmatics randomized to receive medical or surgical treatment has favored surgical therapy as providing the best longterm control of asthma (143). Similar studies in children are lacking and much needed. D.

Complications of GERD

The role of GERD in pediatric airway disease is often difficult to define. As noted above, there is evidence that some airway diseases such as asthma or BPD may contribute to GER and that the refluxed gastric contents could then in turn contribute to further airway disease. Some are skeptical of the contribution of GERD to ongoing airway disease, and the connection, while strongly suspected, is unproven (144). Apart from its role in airway disease, GERD is a pernicious condition itself and deserves vigorous treatment and ongoing follow-up wherever it exists. Among the complications of GERD in the pediatric age group are development of peptic esophageal strictures, bleeding, intractable heartburn, anemia, and Barrett’s esophagus (53). Although it occurs rarely, Barrett’s esophagus may undergo malignant transformation in the child as well as in the adult (144). Thus, GERD must be diagnosed in the child with chronic airway disease and aggressively treated where it is found.

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11 Respiratory Complications of Reflux Disease in Infants

SUSAN R. ORENSTEIN University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania

Infantile apnea and stridor, exacerbations of bronchopulmonary dysplasia and cystic fibrosis, and the pulmonary disease associated with repaired esophageal atresia and diaphragmatic hernia are respiratory diseases affected by gastroesophageal reflux (GER) and presenting in infancy. Nasal regurgitation is a further airway manifestation of reflux essentially limited to infancy. These infantile forms of reflux-associated airway disease are the subject of this chapter. I. Physiology: Infants Versus Older Children and Adults Why are some manifestations of reflux-associated respiratory disease limited to infancy? The answers are to be found in the unique aspects of the infant’s physiology, as well as in the occurrence of congenital disease. These unique aspects of physiology are to be found in the gastrointestinal tract, in the respiratory tract, at the intersection of the two tracts in the pharynx, and in the infant’s body as a whole. They comprise both structural and functional immaturities. A. Gastrointestinal

Similarities between infants and adults with regard to the pathophysiology of reflux are greater than previously suspected, despite marked differences in clinical 269

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manifestations of GER disease (GERD). These similarities include the gastroduodenal secretions that make up the refluxate, the lower esophageal sphincter (LES) tone, and the transient lower esophageal sphincter relaxations (TLESRs), which allow reflux to occur. Soon after birth, term newborn infants are able to secrete enough HCl to drop their gastric pH to 2 and below; peptic activity is similarly mature (1–3). Bile acids and trypsin are also present in the infant’s duodenal contents from birth (4). Lower esophageal sphincter tone is well developed even in premature infants (5). As in adults, TLESRs are the major mechanism for reflux events in infants (6–9). They occur frequently enough that the daily duration of distal esophageal acid exposure is remarkably similar in normal infants and adults (10–12). However, because gastric contents are buffered by infant milk formula for about 2 hours after feedings, pH probe values for acid reflux may significantly underestimate the frequency and duration of total reflux in infants. Despite all of the similarities enumerated above, there are marked differences in gastrointestinal physiology between infants and older people with regard to reflux. These differences include both structural and functional aspects, although much remains to be learned. Structurally, the ratio of esophageal to gastric volume is much less in the infant, so that the esophageal capacity is more easily overwhelmed by reflux (13). This favors regurgitation as a manifestation of reflux disease in infants, and it may make refluxate more accessible to the respiratory tract than in adults. Functionally, gastric and esophageal compliance likely play a role in determining LES and upper esophageal sphincter (UES) relaxation. The much lower gastric compliance in infants than in adults (14) may promote LES relaxation at comparably lower intragastric volumes in infants than in adults. The UES relaxes in infants in response to gastroesophageal reflux (15) and to air insufflation into the esophagus (16); information regarding developmental aspects of esophageal compliance and thresholds for this response are needed. It is possible that the prominence of regurgitation in infants is facilitated by lowerthreshold relaxation of both the LES and UES. Esophageal motor activity is less frequently peristaltic in premature infants than in adults; in the premature infants only about one fourth of esophageal body pressure waves are peristaltic, a finding also true in the near-term babies (5). Such immaturity of esophageal function would impair the return of refluxed material into the stomach and promote its supraesophageal migration. Finally, the oropharyngeal function of infants is immature. The suck-swallow of the infant is different from the complex chewing and bolus manipulation of the mature human. Material regurgitated into the pharynx may thus be less effectively manipulated into a safe location, promoting airway manifestations of GERD in infants.

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The differences in gastrointestinal physiology that provoke reflux-associated respiratory disease in infants are exacerbated by the infant’s diet. This diet is largely liquid, which seems to induce more regurgitation than the thicker consistency of the masticated adult diet. Infants ingest a larger meal compared to their gastric volume than adults do, which also provokes more reflux (17). Furthermore, infants are more apt to manifest allergies to their dietary constituents, and cow milk or soy sensitivity may lead to vomiting and esophagitis, initiating the vicious cycle of esophagitis and reflux. There are several ameliorating factors in the infant diet. It contains little in the way of acid material; infant milk formulas have a pH of nearly 7, compared to many adult beverages with pH ⬍ 3 (18). It is largely isotonic [compared to many adult beverages with osmolalities between 600 and 2600 mOsm/L (18)], and it does not include the refluxogenic effects of caffeine and first-hand tobacco smoke exposure, as many adult diets do. B. Respiratory

The respiratory physiology of infants is also different from adults. The softer, more flexible upper respiratory structures in many babies represent a developmental laryngotracheomalacea, which resolves during infancy. Thus, babies are more susceptible to stridor induced by strong negative pressures during inspiration, a phenomenon that is exacerbated by reflux in some of them. The smaller cross-sectional area of the airway, most exaggerated in the upper airway, is another factor making upper airway symptoms, like stridor, predominate over lower ones in infants, in contrast to the lower respiratory symptom predomination in older children. The fact that young infants are obligate nose breathers makes nasal obstruction by nasal regurgitation or otherwise (e.g., by viral infections or by bedding) a far more hazardous phenomenon in babies than in older individuals. Primitive reflexes are a further aspect of infant physiology that leads to distinct manifestations of reflux-associated respiratory disease. Prolonged apnea is a singular manifestation of reflux in young infants and virtually never occurs in adults. C. Pharynx (Gastrointestinal-Respiratory Intersection)

The structure of the pharynx differs in the infant, in whom the soft palate extends nearly to the larynx, with complex possible effects on swallowing, reflux, and speech (19). This difference may underlie, for example, the frequency of nasal regurgitation in infants (20). The function of the infantile oropharynx does not include the array of airway-protective abilities present in older children and adults. Throat-clearing and other automatic and volitional protections develop during childhood.

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Other Effects

Other differences between infants and adults that impact on reflux are limited gross motor abilities and postural tone. The immature tone of the somatic musculature of the torso and extremities leads to a preponderance of time in the supine position and to slumping postures and increased abdominal pressure when seated. Both supine and slumped-seated positions provoke reflux and impair its gravitational clearance (21,22). Premature infants are particularly hypotonic and may be especially affected by the reflux-provoking effects of such postures. In addition to being unable to stand independently, or even to sit without support during much of infancy, babies are unable to change their position at will in response to symptoms suggesting GERD or respiratory compromise. The youngest infants are unable even to turn over, and premature babies cannot even lift their heads clear of regurgitated material. The ramifications for respiratory sequelae from reflux are obvious.

II. Gastroesophageal Reflux Disease in Infants A.

Disease Course

The course of reflux disease in infants differs considerably from that in older children and adults. Infantile reflux becomes symptomatic during the first months of life but often not until 2–4 months, the peak age of onset. However, it resolves by 12–24 months of age in at least 80% of afflicted babies (23,24). This is in contrast to reflux in older children and adults, which appears anew after infancy. It then tends to persist, waxing and waning symptomatically for years (25,26). B.

Epidemiology

The epidemiology of reflux disease is beginning to be clarified in infants. In the first year of life, nearly 7% of all infants come to medical attention for GER symptoms (27); most receive some treatment, and 1–2% undergo diagnostic evaluation. Less than 1% of infants undergoes antireflux surgery, and the number may be decreasing with improved understanding of nonsurgical therapies. The incidence of symptomatic GERD in very low birthweight infants is higher—3– 10% of such infants have symptoms of reflux-associated apnea, bradycardia, or exacerbated bronchopulmonary dysplasia (28,29). C.

Symptoms

The symptoms of GERD are also different in infants. Many of the unique symptoms of infantile GERD, such as apnea and stridor, are airway manifestations.

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These symptoms may be more acutely dangerous, as well as being more prevalent and more diverse, in infants than in adults. D. Causes for Infant–Adult Differences in Clinical GERD

The differences in clinical presentation in infants have three likely causes: infants’ developmental immaturity, infants’ nonverbal nature, and the chronological brevity of infantile reflux. Developmental immaturity makes regurgitation, apnea, and stridor common manifestations of reflux in infants, whereas they rarely occur in adults (discussed above). The nonverbal nature of infants means that complaints of ‘‘heartburn’’ or other descriptions of esophageal pain do not occur, although intractable crying may be an analogous symptom (30–32). The limited chronicity of reflux in infants minimizes presentations that require chronicity of acid exposure to the esophagus itself, such as erosive esophagitis and stricture. One might even consider infants to manifest the primary pathophysiology of reflux disease more purely, before the vicious cycles and irreversible changes of esophagitis and dysmotility, esophageal shortening and hiatal hernia, scarring and stricture, supervene.

III. Vicious Cycles Between Reflux and Respiratory Disease Reflux provokes respiratory disease by obstructing the respiratory tract. The most primitive conceptualization of how this happens attributed all of the obstruction to gastric material aspirated after being regurgitated into the pharynx. Our sophistication has grown since this concept was first introduced, and we now understand that the respiratory tract may be obstructed at a series of loci by multiple mechanisms, which may occur in concert (33). A. Reflux Causing Respiratory Disease

Actual aspiration of a quantity of gastric material probably occurs only rarely. Even ‘‘microaspiration’’ may be a relatively infrequent event. The lumen of the respiratory tract may be obstructed by its own secretions, however, as well as by aspirated material. In addition, edema of the airway may participate in airway occlusion, and the airway-supporting musculature may contract, represented by laryngospasm or bronchospasm. Gastroesophageal reflux may participate by producing airway motor spasm, edema, or secretions on a reflex basis, as well as by allowing refluxate to reach and occlude the airway. Such reflexes, with afferents in the esophagus and efferents in the airway, have been indicated by pediatric and animal studies, as well as by adult studies (see Chap. 2) (34–40).

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Respiratory Disease Causing Reflux

The other half of the cycle, in which respiratory disease can provoke reflux, involves the provocative effects of positive abdominal and negative intrathoracic pressures. These pressure changes are exaggerated during forced inspiration and expiration, as well as during stridor and coughing. These pressure relationships promote the movement of gastric contents into the esophagus. They are countered by the bolstering effect of the crural diaphragm, which contracts in support of the LES during such straining, if there is no hiatal hernia. Respiratory disease may also provoke reflux more indirectly by prompting the use of therapies that provoke reflux. These therapies include medications, postural drainage, and mechanical ventilation (21,41–49). IV. Respiratory Diseases in Infants The mechanics of infantile respiratory diseases that allow their participation in the vicious cycles indicated above are similar to those in adults. However, several respiratory disorders that are unique to infancy or have their most challenging manifestations during infancy will be briefly discussed individually. A.

Apnea

Apnea has been clearly demonstrated to be temporally correlated with some episodes of reflux and to be experimentally induced by acid infusion into the esophagus (34,35). A large series of infants presenting with apparent life-threatening events (ALTE) found reflux to be responsible for more cases than any other single cause (50). Such reflux-associated apnea usually involves laryngeal closure and can be viewed as an exaggerated protective response to hazardous material threatening the airway (51,52). The relative roles of microaspiration, laryngeal stimulation, and esophageal stimulation in producing apnea have been debated (34,35, 51,53,54). Clinically, reflux-induced apnea is recognized as generally postprandial, occurring in the seated or supine position, apparently obstructive and associated with respiratory efforts, and sometimes associated with oral or nasal regurgitation (55–58). These episodes are generally survived, but occasional deaths have occurred (59). The determination of whether reflux has provoked apnea is a common pediatric diagnostic dilemma. We generally proceed as follows. If a single episode is described as a classic reflux-related event (the infant is postprandial, seated or supine, struggling and turning red and then dusky or pale, and, particularly, if oral or nasal regurgitation is actually seen), we diagnose it without formal investigation. We treat by normalizing feeding volume and frequency, avoiding seated

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and supine positioning, and consider further empiric therapy with thickening of formula, prokinetic medication, and sometimes even empiric acid suppression. If there is recurrence despite such therapy, or if episodes are initially presented as recurrent or as ambiguous with regard to reflux, we perform pH probe with pneumocardiogram (including some measurement of nasal air flow to allow documentation of obstructive apnea). If a clear association is thus demonstrated between reflux and apnea, we augment therapy and consider fundoplication for persisting severe cases, although this is rarely required. If the initial presentation is of central apnea or if the pH probe demonstrates apnea that is clearly unassociated with reflux, we pursue other causes of apnea, such as metabolic or infectious ones, more vigorously (50). B. Stridor

Stridor may represent an incomplete version of obstructive apnea in infants. Because laryngomalacia may be responsible for stridor without participation of reflux (60) clinicians are faced with the decision of whether individual infants with stridor may benefit by antireflux pharmacotherapy or even fundoplication in intractable cases (61–63). Otolaryngologists and pulmonologists have begun to recognize laryngeal changes attributed to GERD during laryngoscopy, although it is not yet absolutely clear that inflammatory changes are due to acid irritation rather than to mechanical trauma in the context of underlying laryngomalacia. While pH probe monitoring (63) or esophageal acid infusion (64) may disclose a temporal association with intermittent stridor, thus prompting therapy of reflux, the relative merits of this approach (evaluation for peptic esophagitis or laryngitis or empiric therapy) are as yet unclear. C. Bronchopulmonary Dysplasia

The participation of chronic lung disease and its therapies in vicious cycles with GERD mandates consideration of reflux as contributing to difficult-to-manage bronchopulmonary dysplasia (BPD) (65–68). Evaluation for esophagitis will select a group for whom antireflux therapy is definitely indicated; in ambiguous cases scintigraphic or bronchoscopic evaluation for aspiration, or empiric pharmacotherapy, may be worthwhile. D. Cystic Fibrosis

Many studies have indicated an increased proportion of infants and children with cystic fibrosis (CF) to have pathological GER (69–81). The underlying reasons for the association, as well as the approach to diagnosis and management, will be similar to infants with BPD. In addition, the increased gastric acidity and the

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malnutrition due to pancreatic insufficiency in CF pose additional problems for the clinician managing infants with CF and GERD. E.

Esophageal Atresia (Tracheoesophageal Fistula)

Esophageal atresia usually occurs with a distal tracheoesophageal fistula, although a small minority of infants may be born with isolated esophageal atresia, isolated tracheoesophageal fistula (‘‘H-type’’), or a proximal fistula. After repair, infants with these anomalies are likely to have GERD for a number of reasons. These are related both to the dysfunctional anatomy postrepair and to congenital disturbances of the antireflux barrier in these infants (82–89). The GERD may induce anastomotic strictures or participate in vicious cycles of reflux and respiratory disease. The difficulty of interrupting the vicious cycle in these children often prompts fundoplication, but fundoplication may be particularly problematic in them because of their esophageal shortening and peristaltic dysfunction due to the atresia itself. F. Diaphragmatic Hernia

Infants born with congenital diaphragmatic hernia usually experience a difficult neonatal course with only about half of live-born infants surviving. They generally have associated pulmonary hypertension, lung hypoplasia, and intestinal malrotation. In addition to surgical repair, extracorporeal membrane oxygenation is often used for weeks before infants are able to wean, due to their associated pulmonary hypertension. Nearly all survivors have clinical GERD, with as many as 20% requiring fundoplication (90). Awareness of the possible contribution of GERD to their chronic lung disease will allow early recognition and a degree of prophylactic intervention. V.

Diagnosis of Reflux in Infantile Respiratory Disease

In addition to the specific diagnostic approaches indicated above, there are some general principles. If chronic or recurrent pneumonia suggests aspiration, the techniques used to diagnose aspiration depend on the institution’s capabilities. Nuclear medicine’s scintigraphy, bronchoscopy evaluating gross appearance and lipid-laden macrophages, or assessment of endotracheal tube for methylene blue instilled in the stomach by nasogastric or gastrostomy tube are all potentially useful. When respiratory symptoms are discrete and recurrent, such as episodes of stridor or cough, one can monitor for the symptom during a 24-hour (or longer) pH probe test. The same phenomenon can be evaluated experimentally and perhaps more efficiently using the modified Bernstein test. A 24-hour pH probe

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alone, without documentation of symptom association, can also be used to define reflux quantity or score as abnormal (and thus both likely to be pathological and likely to warrant therapy). At our institution we frequently use esophageal suction biopsy to diagnose pathologic reflux in infants. The test is rapid, safe, and relatively inexpensive, and in many cases defines the reflux as pathological and thus warranting treatment. Response to antireflux therapy is then used to support the association between the reflux and the respiratory disease. The issue of whether to use empiric therapy for respiratory disease that is suspected to be reflux-associated is a difficult one. This is largely because of the intensity and duration of therapy that have been found to be required to ameliorate most such respiratory disease. VI. Therapy of Reflux in Infantile Respiratory Disease A. Conservative Therapy

Although nonpharmacologic therapy ameliorates reflux symptoms in the majority of infants with reflux symptoms, the addition of pharmacotherapy is necessary for most respiratory disease associated with reflux. Nonetheless, this ‘‘conservative therapy’’ is a crucial underpinning of all treatment. Many infants are overfed at infrequent feedings; simply correcting this error will have dramatic effects on regurgitation. Similarly, thickening of infant feedings with a tablespoon of rice cereal per ounce of formula increases the caloric density by 50% and reduces regurgitation as well. A trial of hypoallergenic elemental formula will also ameliorate symptoms in the babies whose regurgitation initially had an allergic basis, and it might also benefit the occasional infant with an allergic component to the respiratory disease. Avoidance of thin liquids (juices) also benefits reflux, particularly because these juices are usually acidic. Positioning is an important component of antireflux therapy, particularly in young infants, who are unable to change their own position at will in response to symptoms. Supine and slumped-seated positions provoke reflux; we recommend completely avoiding them. This recommendation is in accord with the American Academy of Pediatrics positioning recommendations for prevention of sudden infant death syndrome, which exempts infants with GERD from the ‘‘back-to-sleep’’ campaign. B. Pharmacotherapy

Infants with respiratory disease associated with reflux will generally require both a prokinetic agent and acid suppression, and they may require more intensive therapy for longer durations than infants with simple regurgitation. This corre-

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Table 1 Therapy of Reflux I. Conservative A. Position: prone; or completely upright (avoid supine, semi-seated) B. Thicken infant feedings: 1 tbsp. rice cereal/oz. formula (⫽ 30 cal/oz., if original formula is 20 cal/oz) C. Fast before bed; avoid large meals, obesity, tight clothing D. Avoid foods and medications that lower LES tone or increase gastric acidity: Fatty foods, citrus, tomato, carbonated or acid beverages, coffee, alcohol, smoke exposure Anticholinergics, adrenergics, theophylline, caffeine, calcium channel blockers, prostaglandins II. Pharmacologic a A. Prokinetic: Cisapride (0.2 mg/kg/dose qid: AC, HS) {cramping, arrhythmias} {{concurrent macrolide or antifungal antibiotics—potentially serious arrhythmias}} Metoclopramide (0.1 mg/kg/dose qid: AC, HS) {restlessness, drowsiness, dystonic reactions—antidote; diphenhydramine} {{gastrointestinal obstruction; pheochromocytoma; extrapyramidal risk}} Bethanechol {{avoid in respiratory disease}} B. Antacid: Cimetidine (5–10 mg/kg/dose qid: AC, HS) {headache, pancytopenia, gynecomastia, cholestasis} Ranitidine (2–3 mg/kg/dose tid) {similar to cimetidine, less gynecomastia, more hepatitis} Famotidine (0.5 mg/kg/dose bid or tid; adult 40 mg HS) Omeprazole (0.7–3.3 mg/kg/dose qd or divide bid; adult 20 mg HS or bid) Antacid (0.5–1 cc/kg/dose, 3–8⫻/day: 1–2 hr PC,HS) {diarrhea, constipation, rickets, Al or Mg toxicity} C. Barrier or miscellaneous mechanism: Sucralfate slurry (1 g in 5–15 ml solution, qid: PC, HS)—protects against bile salts, trypsin, acid {constipation, gastric concretions, potential binding of other medications} Alaginic acid-antacid (2 g 3–8⫻ a day: PC) III. Surgical A. Fundoplication (complete vs. loose wrap; ⫾gastrostomy, ⫾pyloroplasty; laparotomy vs. laparoscopy) B. Gastrojejunostomy (), Common doses; {}, partial list of side effects; {{}}, partial list of contraindications. a Usual course is 8 weeks. Source: Adapted from Ref. 97.

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sponds to adult data suggesting the need for particularly vigorous therapy to interrupt the reflux-respiratory vicious cycles (91). Table 1 indicates typical doses and other aspects of pharmacotherapy. C. Surgical Therapy

Nissen fundoplication is the most effective antireflux therapy and thus is lifesaving for some children with intractable reflux-associated respiratory disease (92– 95). Its long-term efficacy is incomplete, however, and a number of side effects and complications prevent it from being a panacea. Some of its problems are particularly pronounced in infants with respiratory disease, such as, herniation of the wrap due to exaggerated abdominothoracic pressure relationships or dysphagia in children who have the underlying esophageal dysmotility associated with repaired esophageal atresia. Newer forms of surgical intervention in GERD have also been applied to infants: gastrojejunostomy (96) and laparoscopic fundoplication. Their advantages and disadvantages are debated, and their use must be individualized, both to the patient and to the surgeon. Gastrojejunostomy disrupts less of the normal anatomy and physiology but probably requires ongoing antireflux pharmacotherapy to be maintained as well.

VII. Conclusion Increasing recognition of the association between a variety of respiratory diseases and gastroesophageal reflux in infants will permit us to better identify and treat it. Thus we can prevent morbidity and mortality in these individuals who have many decades of potential health ahead of them.

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12 Oral Manifestations of GERD

DAVID A. LAZARCHIK and STEVEN J. FILLER University of Alabama School of Dentistry Birmingham, Alabama

I. Introduction A multitude of extraesophageal manifestations have been associated with gastroesophageal reflux disease (GERD). These include asthma (1), chronic coughing (2), dyspnea (3), laryngitis (4), recurrent pneumonitis, pharyngitis, and laryngeal carcinoma (5). Although the effects of various acidic substances on the oral cavity have been known for many years, only more recently has gastric acid been recognized as a cause of oral disease. Gastrointestinal disorders such as malabsorption syndrome in children (6), voluntary reflux phenomenon (rumination) (7), and subclinical regurgitation associated with chronic alcoholic gastritis (8) and eating disorders associated with chronic vomiting [anorexia nervosa and bulimia (9)] have been linked to damage to dental hard tissues. Howden (10) documented dental erosion in a patient suffering from hiatus hernia, one of the first reports of the effects of GERD on the oral cavity. Dental erosion can be considered to be the predominant oral lesion associated with GERD. Because of the subtle changes in the early stages of erosion, the multifactorial etiology of the lesion, and the many factors that may modify the effects of gastric acid, diagnosis of GERD-associated erosion can be problematic. Early intervention is very important in avoiding chronic damage to the dentition. Such damage can 285

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be severe and debilitating and require extensive and formidable dental rehabilitation. II. Oral Soft Tissue Manifestations A.

Mucosal Lesions

Damage to the esophageal mucosa as a result of gastric reflux can lead to erosive esophagitis and the development of strictures (11). Extension of such injury to the oral mucosa might be expected but has not been extensively documented. In one study (12) the orodental status of 109 patients with upper gastrointestinal symptoms was examined. Approximately 55% of patients with reflux esophagitis reported mouth symptoms such as burning mouth sensation, sensitivity in the tongue, and painful ulcers. Pathognomonic oral lesions were not observed in the patients studied. In another study (13) oral, dental, and salivary parameters in 117 patients with reflux disease were evaluated. The majority of patients reported frequently suffering from dry mouth, dentinal hypersensitivity, nonspecific itching/burning sensations in the mouth, and/or pharyngeal symptoms. Again, pathognomonic lesions were not reported, and no significant differences existed between dental erosion and erosion-free groups. Because of the lack of studies in this area and the many possible etiologies of the mucosal lesions and symptoms, one cannot make firm conclusions regarding such lesions in GERD patients. B.

Periodontal Manifestations

Other oral soft tissue manifestations such as gingivitis and periodontitis have also received little or no study. No correlation has been found between PI (plaque index, an indicator of oral hygiene status commonly used in clinical dental studies) or GI (gingival index, a measure of gingival inflammation) and GERD as diagnosed by 24-hour esophageal pH levels (14). In other groups suffering from chronic oral acid exposure (bulimics and anorexics), CPITN (Community Periodontal Index of Treatment Needs, an indicator of periodontal health and extent of therapy indicated) and PI were measured as part of a larger study of other oral and dental complications (15). The study group actually showed lower plaque scores than the control group but had significantly more gingival recession and periodontal bleeding sites. There was no difference between groups in the presence of destructive periodontal disease as characterized by deeper periodontal pockets. C.

Salivary Gland Manifestations

Salivary gland enlargement, especially enlargement of the parotids, is a complication seen in chronic regurgitation which might potentially be seen in GERD pa-

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tients. Brady (16) noted parotid enlargement in up to 10% of bulimics, especially frequent in those bingeing and vomiting one or more times per day. Fifty percent showed elevated serum amylase levels, the significance of which has not been explained. Proposed mechanisms for salivary enlargement include ‘‘work hypertrophy’’ due to intense repeated glandular stimulation and irritation of the epithelial linings of the salivary ducts by repeated exposure to gastric acid. One might expect similar, though possibly less severe, enlargement in patients suffering from the most severe forms of chronic GERD. Such patients should be carefully examined for such a finding. III. Hard Tissue Manifestations A. Tooth Erosion

In contrast to the limited documentation of soft tissue manifestations, tooth erosion as a manifestation of chronic GERD has been more extensively studied. Dental erosion, the primary oral manifestation of chronic GERD, is defined as the loss of tooth substance by chemical process (usually acid exposure) not involving bacteria (17). The initial stages of erosion are extremely difficult to detect. The earliest change is a loss of surface sheen with the development of a frosted glass appearance of the enamel surface of the tooth. This initial finding can best be detected when the teeth are completely dry. Gradually, as the erosion process continues over years, the developmental features on the enamel surface are corroded away. Pits, fossae, and primary and secondary grooves normally found on the occlusal (biting) surfaces of molars and bicuspids become rounded out and lose their characteristic definition. The facial (outside) and lingual (inside) surfaces of exposed teeth begin to erode, leaving a smooth, cupped-out lesion with well-defined borders. Once the outer layer of enamel is eroded through, the softer and less acid resistant dentinal layer is exposed (Fig. 1). This layer deteriorates more rapidly, and exposure of the dentin often results in hypersensitivity to thermal change, sweets, and dietary acids. Such hypersensitivity is frequently refractory to treatment. As the erosive process continues, tooth substance is lost around existing restorations, and the appearance of amalgam fillings ‘‘standing proud’’ is characteristic of the process (Fig. 2). Severe cupping of occlusal and incisal surfaces can result in the appearance of an enamel shell surrounding a dished out dentinal surface (18) (Fig. 3). Diagnosis of erosion can be complicated by the presence of other lesions such as abrasion and attrition, which also result in a gradual loss of enamel and dentin. B. Classification System

One of the difficulties in comparing different studies of dental erosion is the lack of standardization of classification systems for judging the severity of the lesions.

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Figure 1 Lingual view of maxillary incisors. Dished-out lesions with enamel eroded through to dentin surface.

The most widely used system was developed by Eccles and Jenkins in 1974 (19). It is based on clinical appearance and involves evaluating the loss of surface characteristics and the depth of lesions for each tooth surface judged (Table 1). Numerical grades are assigned based on the following criteria: Grade 0 ⫽ no detectable erosion; Grade 1 ⫽ loss of normal surface features with resulting smooth, glazed surface, but lesion confined to enamel; Grade 2 ⫽ enamel eroded exposing dentin on less than one third of the surface; Grade 3 ⫽ exposure of dentin on more than one third of surface. Use of this system has allowed consistency in evaluation among studies. C.

Etiology/Prevalence in the General Population

Tooth erosion has been recognized in the dental literature for over 200 years and has been associated with a multitude of causes both extrinsic and intrinsic. One of the earliest identified extrinsic causes was exposure to acids used in chemical and manufacturing industries. Other extrinsic factors include dietary acids found in citrus fruits, soft drinks, vinegar, and sports drinks, certain medicines such as vitamin C and iron tonic preparations (20), gas chlorinated swimming pool water (21), and even certain types of oral hygiene swab-sticks intended for institutional

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Figure 2 Erosion on occlusal surfaces of mandibular posterior teeth. Loss of tooth structure surrounding restorations gives appearance of amalgams ‘‘standing proud’’ (arrows).

use (22). As previously mentioned, intrinsic causes of dental erosion can include any gastrointestinal or psychological disorder associated with chronic vomiting or gastric reflux. The reported prevalence of dental erosion in the general population varies widely. Pindborg (13) reported in 1970 that 2% of 1345 U.S. males examined had erosion. Brady and Wood (23) examined the labial tooth surfaces of 900 dentists and reported 5.3% with cervical erosions. Sognnaes et al. (24) examined 10,000 extracted teeth and reported an 18% incidence of erosion-like lesions. A more recent study of 391 Swiss adults (25) showed an overall prevalence of 16% with at least one tooth demonstrating evidence of facial erosion. The variation in reported results of these studies can be explained by the different populations studied, the lack of a clear distinction between erosion and other similar lesions, the differences in tooth surfaces studied, and the differences in erosion grading systems used. D. Erosion in GERD Patients

A few studies have attempted to establish a relationship between dental erosion and GERD. In one, erosion was detected in 20% of patients diagnosed with either

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Figure 3 Lingual view of mandibular incisors. An enamel shell surrounds the cupped-out remaining dentin surface (arrow).

reflux esophagitis or duodenal ulcer. It was concluded that dental erosion might be linked with gastrointestinal disorders, which result in increased gastric acid output (12). Interestingly, no erosions were found in patients with duodenogastric reflux in the study group who had undergone cholecystectomy. The authors surmised that alkaline duodenogastric reflux in these patients may have reduced

Table 1 Eccles and Jenkins Erosion Grading System Rating

Definition

Grade 0

No erosion

Grade 1 Grade 2

Enamel only Dentin exposure less than 1/3 surface Dentin exposure more than 1/3 surface

Grade 3

Source: Ref. 19.

Clinical appearance Normal; enamel shiny with normal surface characteristics Loss of surface characteristics; glazed appearance Concavities at tooth cervix; smooth, dished-out lesions more wide than deep Cupping of incisal edges and cusp tips; amalgams ‘‘stand proud’’ above adjacent tooth structure

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the acidity of gastric contents. The medical diagnosis in this study was done by gastroscopy. Other studies using esophagogastroduodenoscopy with biopsy to diagnose reflux disease detected a similar rate of dental erosion (24%) (13). Patients with erosion were older and the mean duration of their reflux disease was longer as compared to those without erosion. A more direct link between acid reflux and tooth erosion has been explored using 24-hour esophageal pH monitoring (26). Fifty-five percent of patients with reflux as diagnosed by pH testing had dental erosion. Eighty-three percent of patients with idiopathic dental erosion referred by dentists for pH testing had abnormal reflux. The authors of this study felt that the connection was so strong that dental erosion should be considered an atypical manifestation of GERD. Others have attempted to further strengthen the association by proving the presence of acid in the oral cavity at the same time gastric reflux episodes were occurring (27). Intraesophageal and intraoral pH were simultaneously monitored for 24 hours in patients with tooth erosion of unknown etiology. Unexpectedly, changes in oral pH were not detected concurrent with reflux even during long supine reflux episodes. However, only 21% of the patients who underwent pH monitoring were judged to have pathologic acid reflux. Eighty percent who had severe erosion also had low salivary buffer capacity. It was suggested that dietary acids in this study group of young males and their low salivary buffer capacity may have been the cause of erosion, not reflux episodes. The conflicting results in these studies can be attributed to variations in study group size and composition and the multitude of possible causes of erosion (especially extrinsic sources) and modifying factors such as saliva quantity and quality. It has also been suggested that erosion only becomes evident in patients with severe, long-duration (over 15 years) reflux disease. With milder GERD, acid reflux either is not propelled all the way to the oral cavity or is rapidly cleared or neutralized by normal physiologic mechanisms.

IV. Relationship of Dental Erosion to Salivary Parameters Enamel dissolves at a critical pH of approximately 5.5, well above the estimated pH of less than 2.0 of gastric refluxate (28). Because of the loss of ameloblasts (enamel-forming cells) upon eruption of the tooth into the mouth, dental enamel has no capacity to repair itself when damaged by the propulsion of gastric refluxate into the oral cavity. However, the same salivary parameters that have been shown to play a protective role against acid challenge in the esophagus may modify the effects of gastric acid on oral tissues. It has been shown that saliva flow can double in esophagitis patients with the onset of heartburn and may play an important role in clearing refluxed gastric acid from the esophagus (29) and presumably from the oral cavity. Chemical and mechanical stimulation of esopha-

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geal mucosa results in a dramatic increase in salivary flow, pH, and viscosity, all factors related to a protective mechanism in the esophagus (30). Thus, saliva may play a protective role in the oral cavity by the maintenance of a neutral pH via physical flow and resulting lavage of acid. Saliva may also help maintain tooth integrity by remineralization of early subsurface lesions from its supersaturated solution of calcium phosphate salts (31). Whether dental erosion occurs in the GERD patient may depend on whether the balance of acid challenge versus protective salivary factors is upset. Some studies have shown that patients with severe idiopathic erosion have dramatically lower unstimulated salivary flow rates (32) and a higher mucin content. It has been estimated that patients with low unstimulated salivary flow rate are at a five times greater risk of suffering dental erosion than those with normal flow rates (20). Elevated mucin levels may prevent the precipitation of calcium phosphate salts, which repair enamel demineralization (33). Others have shown that a significantly greater number of erosion patients have a lower saliva buffer capacity than controls (34). It has been suggested that abnormal buffer capacity allows greater injury to oral tissues by gastric acid. This theory of the protective role of saliva against the effects of gastric acid on the oral cavity remains untested; erosion patients in some studies have had normal salivary parameters (35). V.

Differential Diagnosis of Dental Erosion

As mentioned previously, the most prominent oral condition noted in some GERD patients is that of tooth erosion. Unfortunately, the clinician is often faced with considerable difficulty in differentiating dental erosion from other similar appearing oral hard tissue lesions. Additionally, once the diagnosis of dental erosion is made, tying the condition to GERD may not be as simple as one would wish. Because a variety of internal and external factors may also cause dental erosion, a rather detailed dental examination as well as a nutritional and medical history must be gathered from the patient to establish the etiology. In the patient with severe, extensive dental erosive lesions, the diagnosis is usually much easier, but the etiology may still remain obscure. With good examination techniques, proper patient questioning, and appropriate testing, the astute clinician can usually obtain a reliable diagnosis. A.

Dental Caries

Like dental erosion, dental caries is also caused by acidic attack on tooth structure. The acid in this case is produced by colonies of bacteria (Streptococcus mutans, Lactobacillus, and some species of Actinomyces), which attach to the tooth. The appearance of caries differs considerably from patient to patient and location to location, but it is generally not difficult to differentiate caries from

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dental erosion. Caries (Fig. 4) will usually present as irregular, cavitated areas found predominantly between teeth and on their chewing surfaces. These areas are soft, sticky when probed, and frequently exhibit some type of colored debris. The colors range from the usual tans and browns to the less-seen greens, oranges, and black. Patients with easily observed caries will also tend to exhibit signs of poor dental hygiene such as inflamed, hemorrhagic, and receded gingiva, as well as plaque and calculus accumulation. Although caries may involve extensive areas of the tooth, the lesions are generally more limited than those of erosion, which will be seen broadly covering the tooth surface with a smoother, more uniform loss of tooth substance. B. Attrition

Attrition (Fig. 5) can be defined as the natural, physiological, and sometimes pathological wearing down of teeth over time. As such, it can only be seen in areas where teeth touch. This is unlike dental erosion, which will be seen on any tooth area sufficiently exposed to acidic substrate. A frequent feature in older dentitions, attrition is often seen in combination with tooth erosion. Where areas of attrition and erosion overlap, it will be difficult, if not impossible to differenti-

Figure 4 Dental caries. Note rough irregular margins of debris-filled lesions as opposed to clean, smooth erosion lesions of previous figures.

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Figure 5 Attrition on occlusal and incisal surfaces of mandibular teeth. Enamel layer has been completely lost on incisors exposing dentin. Pulp chambers are visible on some teeth (arrow).

ate between the two. To establish erosion as a diagnosis, the clinician should look for areas that exhibit those lesions exclusive of areas of occlusion. Attrition can be expedited by pathological habits. This may occur as the result of habitual clenching, grinding, or repetitive tapping of teeth together. The oral results of habits of forced clenching and bruxing (Fig. 6) are frequently confused with those of dental erosion.

C.

Abrasion

Abrasion is defined as the pathologic wearing away of tooth substance (36) and is most often secondary to harmful habits involving various materials such as metal, plastic, and wood. This includes the improper use and oral manipulation of toothpicks, toothbrushes, pencils, pens, bobby pins, and other items. Tooth abrasion is generally not confused with dental erosion because it tends to be very localized on specific teeth and usually takes the form of grooves, chips, and wedges (Fig. 7). Abrasion, attrition, and erosion often appear together as a triad of similar, difficult-to-separate conditions. However, they can often be distinguished

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Figure 6 Effects of bruxism. Note wear of incisal edges in a straight line establishing flat plane of occlusion. Teeth have lost 50% or more of their normal incisal length.

from each other by detailing the dental history and carefully noting the location of the lesions. D. Relationship of Etiology to Location

The position and surfaces of teeth affected by erosion can provide valuable clues as to the origin of the problem. Anatomical considerations, such as conformity of the cheek to the teeth as well as the size and positioning of the tongue, may protect some tooth surfaces from attack. This varies from patient to patient, but with intrinsically produced erosions (e.g., GERD, bulimia, and chronic vomiting) one would expect to find more significant erosions on the lingual and occlusal surfaces of teeth (37) (Table 2). Because of protection from the tongue, the lingual of the maxillary arch (particularly behind the incisors) is often affected to a greater extent than the mandibular arch. Dental erosion produced by extrinsic sources (e.g., overuse of citrus fruits and their products and environmental acid exposures) tends to be most visible on the facial surfaces of teeth or the occlusal surfaces. Although possible, lingual erosions are much less likely. In severe cases (intrinsic or extrinsic) the entire dentition will show signs of erosion (Fig. 8). Since specific tooth erosions are indistinguishable from each other, any link to

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Figure 7 Abrasion. Overvigorous use of hygiene aids has worn grooves into root surfaces of teeth after exposure by gingival recession secondary to periodontal disease.

Table 2 Erosion Etiology Related to Oral Location Erosion source Intrinsic: GERD Bulimia Chronic vomiting Extrinsic: Overuse of citrus products Environmental/ occupational

Teeth/surfaces most affected Lingual surfaces of anterior maxillary and mandibular teeth; occlusal surfaces of all teeth

Facial surfaces of maxillary teeth; occlusal surfaces of all teeth

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Figure 8 Severe erosion with resulting loss of entire plates of enamel (arrows) on the facial surfaces of maxillary anterior teeth.

a cause, such as GERD, is made by noting location, taking a thorough dental and medical history, and carrying out appropriate medical testing. VI. Prevention of Oral Manifestations Over the years, dentists and others have developed a number of methods in an attempt to prevent loss of tooth material due to reflux of gastric acids. It should be obvious to the reader that these methods are temporary measures or are utilized when adequate medical control of the condition is not accomplished. The preferred method for preventing oral manifestations of GERD is medical control of the disease. Without that control, dental methods meet with limited success, and progression of the erosion, although frequently slowed, will continue. A. Acid Neutralization

In those individuals with GERD who are immediately aware of symptoms subsequent to a reflux episode, there may be value in attempting to neutralize the acidic refluxate orally. This can be accomplished by encouraging the patient to quickly

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rinse with a solution of sodium bicarbonate or magnesium hydroxide or by immediately taking antacid tablets. It has been suggested that allowing antacids to slowly dissolve in the mouth before swallowing them may better neutralize acid and protect the oral tissues (38). Care should be taken to select sugar-free products. Toothbrushing should be delayed for at least one hour after a reflux episode as it may damage acid-weakened enamel. Since masticatory stimulation has been shown to cause profound increases in salivary pH and bicarbonate levels (39), chewing sugar-free gum may help stimulate salivary flow and neutralize oral acid. B.

Physical Barriers

Various materials (e.g., acrylic, vinyl, silicone, and polyethylene) can be utilized to construct a physical barrier to prevent as much refluxate as possible from contacting teeth. These ‘‘mouth guards’’ fit snugly over the tooth surfaces and when properly monitored by dental personnel can be worn over long periods of time. They should especially be worn during reflux episodes and at night, when diurnal variations cause a decrease in salivary flow and buffering capacity (40). An additional benefit to the patient is the ability of the device to function as a carrier for tooth-protective fluoride gel (1.1% neutral sodium fluoride). C.

Saliva Stimulation

Decreased amounts of saliva jeopardize the patient’s oral health in many ways. Saliva not only provides a lubricating effect, thereby reducing tooth-to-tooth friction and resulting in tooth substance loss, but it also serves to dilute and buffer acidic attack from any source, including the bacteria of dental caries. Xerostomia in the patient with significant GERD problems will increase oral complications and hasten the process of dental erosion. Artificial salivas are available (e.g., Xero-Lube, Salivart, Moi-stir), but patient compliance is critical and often difficult to maintain over time. Since many medications contribute to decreased saliva flow, it is recommended that patients be queried about dry mouth and, wherever possible, alternative medications utilized. Of drugs used to treat GERD, omeprazole has been shown to cause reduced salivary flow in some patients (41). Salivary stimulants such as pilocarpine may be appropriate to utilize with some patients. VII. A.

Treatment of Oral Manifestations Soft Tissue Lesions

Palliative measures can be taken for patients who complain of burning mouth sensations or painful ulcers. Various combinations of coating agents and topical

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anesthetics have been used: a 50/50 mix of diphenhydramine and attapulgite (Kaopectate), 2% viscous lidocaine, and 0.5% dyclonine hydrochloride. Oral ulcers can be treated with Orabase with benzocaine or Zilactin gel. B. Dental Erosion

Indication for Treatment

Dental restorative treatment is indicated in those GERD patients with sufficiently affected dentitions to produce tooth pain and/or sensitivity, functional, or cosmetic problems. Not all affected teeth require treatment, and when restoration is necessary, a conservative treatment approach is recommended. If the patient’s reflux problem is under good medical control and the patient does not report pain, function, or cosmetic concerns, dental treatment should be limited. On the other hand, continued progression of the loss of tooth structure will require active intervention on the part of a dentist. The extent of this treatment will depend on the nature of the problem and the extent of the destruction. Patients with a history of GERD should be monitored for dental erosion throughout their life and dental treatment instituted when appropriate. Dental Treatment Options

Patients exhibiting less severe tooth erosion often do well with simple toothcolored dental restorations (glass ionomers, composites, or ‘‘bonding’’) that restore tooth contours and serve to protect the underlying structure from further acidic attack. Some of these materials contain fluoride, which provides additional protection for the tooth. Teeth that have lost large amounts of enamel and dentin often require more extensive and aggressive dental care. Following additional shaping of the teeth, a dentist will prepare partial or complete metal and/or porcelain coverings for the teeth (crowns). If the tooth pulp has been compromised, endodontic treatment (root canal therapy) will be required or the tooth may require extraction. For severe dental erosion cases, patients will require full mouth rehabilitation with multiple crown units and perhaps bridges. Unfortunately, the financial burden of such extensive dental care necessitates that many patients seek extraction of teeth and construction of a removable prosthetic appliance. VIII. Conclusion Although dental erosion has been studied for years, we are just beginning to understand its relationship to GERD. Little data exist about the effects of gastric refluxate on the oral soft tissues, and the data about hard tissue manifestations are often confusing. This is because of the many possible etiologies of erosion, the difficulty of diagnosing erosion in the presence of other lesions of hard tooth

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structure, and the interplay of modifying factors such as salivary parameters, the duration and severity of reflux, and exposure to extrinsic causes of erosion. The combined efforts of physicians (in controlling or minimizing reflux) and dentists (in preventing and treating oral lesions) are necessary if the patient is to avoid the devastating dental consequences of chronic GERD. References 1. 2.

3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

13. 14. 15. 16. 17. 18.

Simpson WG. Gastroesophageal reflux disease and asthma: diagnosis and management. Arch Intern Med 1995; 155(8):798–803. Ludviksdottir D, Bjornsson E, Janson C, Boman G. Habitual coughing and its associations with asthma, anxiety and gastroesophageal reflux. Chest 1996; 109(5):1262– 1268. Field SK, Underwood M, Brant R, Cowie RL. Prevalence of gastroesophageal reflux symptoms in asthma. Chest 1996; 109(2):316–322. Pope CE. Current concepts: acid-reflux disorders. N Engl J Med 1994; 331(10):656– 660. Kahrilas PJ. Gastroesophageal reflux disease. JAMA 1996; 276(12):983–988. Ansaldi N, Morabito A, Balocco P, Galleano E. Dental changes in children with malabsorption. Minerva Pediatr 1989; 41:581–585. Gilmour AG, Beckett HA. The voluntary reflux phenomenon. Br Dent J 1993; 175: 368–372. Smith BGN, Robb ND. Dental erosion in patients with chronic alcoholism. J Dent 1989; 17:219–221. Roberts MW, Shou-Hua L. Oral findings in anorexia nervosa and bulimia nervosa: a study of 47 cases. J Am Dent Assoc 1987; 115:407–410. Howden GF. Erosion as the presenting symptom in hiatus hernia. Br Dent J 1971; 131:455–456. Brown CM, Rees WD. Review article: factors protecting the oesophagus against acid-mediated injury. Alim Pharm Ther 1995; 9:251–262. Jarvinen V, Meurman JH, Hyvarinen H, Rytomaa I, Murtomaa H. Dental erosion and upper gastrointestinal disorders. Oral Surg Oral Med Oral Pathol 1988; 65:298– 303. Meurman JH, Toskala J, Nuutinen P, Klemetti E. Oral and dental manifestations in gastroesophageal reflux disease. Oral Surg Oral Med Oral Pathol 1994; 78:583–589. Schroeder PL, Filler SJ, Ramirez B, Lazarchik DA, Vaezi MF, Richter JE. Dental erosion and acid reflux disease. Ann Intern Med 1995; 122:809–815. Touyz SW, Liew VP, Tseng P, Frisken K, Williams H, Beumont PJV. Oral and dental complications in dieting disorders. Int J Eating Disord 1993; 14:341–348. Brady JP. Parotid enlargement in bulimia. J Fam Pract 1985; 20(5):496–502. Pindborg JJ. Chemical and physical injuries. In: Pindborg JJ, ed. Pathology of the Dental Hard Tissues. Philadelphia: WB Saunders, 1970:312–325. Bevenius J, L’Estrange PL. Chairside evaluation of salivary parameters in patients with tooth surface loss: a pilot study. Aust Dent J 1990; 35:219–221.

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19. Eccles JD, Jenkins WG. Dental erosion and diet. J Dent 1974; 2:153–159. 20. Jarvinen VK, Rytomaa II, Heinonen OP. Risk factors in dental erosion. J Dent Res 1991; 70:942–947. 21. Filler SJ, Lazarchik DA. Tooth erosion: an unusual case. Gen Dent 1994; 42:568– 569. 22. Meurman JH, Sorvari R, Pelttari A, Rytomma I, Franssila S, Kroon L. Hospital mouth-cleaning aids may cause dental erosion. Spec Care Dent 1996; 16(6):247– 250. 23. Brady JM, Wood RD. Scanning microscopy of cervical erosion. J Am Dent Assoc 1977; 94:726–729. 24. Sognnaes RF, Wolcott RB, Xhonga FA. Dental erosion I. Erosion-like patterns occurring in association with other dental conditions. J Am Dent Assoc 1972; 84:571– 576. 25. Lussi A, Schaffner M, Hotz P, Suter P. Dental erosion in a population of Swiss adults. Commun Dent Oral Epidemiol 1991; 19:286–290. 26. Schroeder PL, Filler SJ, Ramirez B, Lazarchik DA, Vaezi MF, Richter JE. Dental erosion and acid reflux disease. Ann Intern Med 1995; 122:809–815. 27. Gudmundsson K, Kristleifsson G, Theodors A, Holbrook WP. Tooth erosion, gastroesophageal reflux, and salivary buffer capacity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995; 79: 185–189. 28. DeMeester TR, Johnson LF, Joseph GJ, Toscano MS, Hall AW, Skinner DB. Patterns of gastroesophageal reflux in health and disease. Ann Surg 1976; 184:459– 470. 29. Helm JF, Dodds WJ, Hogan WJ. Salivary response to esophageal acid in normal subjects and patients with reflux esophagitis. Gastroenterology 1987; 93:1393–1397. 30. Namiot Z, Rourk RM, Piascik R, Hetzel DP, Sarosiek J, McCallum RW. Interrelationship between esophageal challenge with mechanical and chemical stimuli and salivary protective mechanisms. Am J Gastroenterol 1994; 89(4):581–587. 31. Mandel ID. The role of saliva in maintaining oral homeostasis. J Am Dent Assoc 1989; 119:298–304. 32. Wolgtens JHM, Vingerling P, de Blieck-Hogervorst JMA, Bervoets D. Enamel erosion and saliva. Clin Prev Dent 1985; 7:8–10. 33. Mannerberg F. Saliva factors in cases of erosion. Odont Revy 1963; 14:156– 166. 34. Gudmundsson K, Kristleifsson G, Theodors A, Holbrook WP. Tooth erosion, gastroesophageal reflux, and salivary buffer capacity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995; 79:185–189. 35. Schroeder PL, Filler SJ, Ramirez B, Lazarchik DA, Vaezi MF, Richter JE. Dental erosion and acid reflux disease. Ann Intern Med 1995; 122:809–815. 36. Shafer WG, Hine MK, Levy BM. A Textbook of Oral Pathology. 3d ed. Philadelphia: WB Saunders, 1974. 37. Jarvinen V, Rytomaa I, Meurman JH. Location of dental erosion in a referred population. Caries Res 1992; 26:391–396. 38. Meurman JH, Kuittinen T, Kangas M, Tuisku T. Buffering effect of antacids in the mouth—a new treatment of dental erosion? Scan J Dent Res 1988; 96(5):412–417.

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13 Odds and Ends and the State of the Art

MARK R. STEIN University of South Florida College of Medicine Tampa, Florida

This final chapter will initially focus on information not covered elsewhere. It includes a review of gastroesophageal reflux disease (GERD) in the geriatric population as well as in the pregnant patient. An attempt to coordinate significant information from other chapters will follow and will focus on where we are today in the evaluation and treatment of GERD and airway disease. If you have read this book or selected chapters, you know that a large volume of information from multiple disciplines has been used to weave a tapestry of GERD-induced airway diseases. Starting with the embryo (Chap. 1) and progressing from infancy (Chap. 11) and childhood (Chap. 10) to the adult (Chaps. 4,5,6–8) and geriatric populations (Chap. 13), this volume attempts to follow the evolving relationships between the gastrointestinal tract and respiratory tract. It also follows the consequences of GERD from the mouth and dentition (Chap. 12) to the nasopharynx, larynx (Chaps. 4,5), and lungs (Chaps. 6–11). With the high prevalence of both GERD and airway disease in the population, a practicing physician usually sees at least one patient daily with these problems. The intent of this book is to awaken us to the concept that GERD, sometimes silent, can cause a variety of symptoms, and these relationships should always be considered in approaching the patient with airway disease. This is particularly important when the airway disease does not respond to a usually effective course of treatment. This concept helps us to better understand how GERD can contribute to the etiology of diseases and conditions previously considered idiopathic (see Chaps. 4,7,10–12). 303

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GERD in the Geriatric Patient

The evaluation of GERD and airway disease in the geriatric population is especially complex. This complexity is due to the normal physiologic changes that occur with aging and the occurrence of additional diseases, which can complicate both diagnosis and treatment (1,2). The geriatric patient may have recent onset of GERD related to changes in weight, diet, or lifestyle, or he or she may have had longstanding GERD. Patients with many years of GERD may present with numerous complications or manifestations of this condition (see Chaps. 4,5,7,12). Figure 3 in Chapter 9 shows an outline for the progression of GERD from upright to supine and then bipositional reflux. The DeMeesters explain the changes based on tissue damage from bile salts in the refluxate causing further tissue damage. The older the patient with GERD and the longer he or she has had GERD, the greater are the chances that he or she will have these progressive changes. As always, diagnosis starts with a good history. Unfortunately, a single question (Do you have heartburn?) is not likely to uncover this diagnosis, especially if the reflux is silent (no heartburn). After reviewing complex surveys for GERD (3), I have used the questionnaire shown in Table 1 for several years. This questionnaire has been easy to use and extremely helpful in obtaining clues to the presence of GERD and several of the supraesophageal manifestations of GERD. This questionnaire is most valuable in adults, since children often have problems communicating their symptoms. It helps to alert the clinician to a variety of possible otolaryngologic and lower respiratory problems, while relating symptoms to daily activities. The geriatric patient, like younger patients, will often present with a variety of symptoms (e.g., cough, sore throat, episodic throat closing, and asthma), all of which may be due to GERD. Sometimes a questionnaire of this type will draw attention to this relationship. Often a patient of this type will be seen by multiple specialists, each of whom looks at only one aspect of the patient’s problems without seeing the whole picture. This is a greater problem today with managed care, since the specialist may have a limited number of visits to arrive at a diagnosis and treatment plan. As explained in Chapter 4, the evaluation may differ based on the initial symptoms with supraesophageal symptoms, often requiring a dual pH probe study for correct diagnostic information, particularly in laryngeal diseases and with cough (see Chaps. 4,5) (4,5). Evaluation of the geriatric patient with respiratory problems must be complete when suspecting GERD. The physical examination gives a few clues, including the dry rales of pulmonary fibrosis and the wet rales of a recent episode of aspiration. Extremely late findings include clubbing and increased anteroposterior chest diameter, which are often found with other types of lung disease. Pulmonary function testing is helpful in establishing the initial degree of restrictive and ob-

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Table 1 Gastroesophageal Reflux Questionnaire for Patients with Cough, Sinusitis, Wheeze, or Voice Changes Do you have 1. Heartburn or indigestion? How often? 2. Regurgitation of stomach contents (stomach contents coming into your mouth)? How often? 3. Use of antacids (Rolaids, Tums, Maalox)? How often? 4. Vomiting easily or frequently? 5. Frequent burps or hiccups? 6. Chronic cough worse after meals? 7. Chronic cough worse after lying down? 8. Chronic hoarseness or voice change? 9. Chronic sinus disease? 10. Chest pains? 11. Stomach pain? 12. Neck pain? 13. Sore throat frequently? 14. Feelings of throat closing or something stuck in throat? 15. Adult-onset asthma? 16. Asthma not relieved with usual treatments? 17. Asthma worse after meals, alcohol, lying down, bending to tie shoes, or after onset of heartburn? 18. Worse heartburn after theophylline? 19. Anemia?

Yes

No

Not sure

structive changes and responsiveness to bronchodilators. Follow-up testing will gauge the additional responsiveness to inhaled or systemic steroids and treatment of GERD. A persistent residual restrictive component may suggest that aspiration has led to fibrosis. Nasopharyngoscopy with direct laryngoscopy has lead to a far greater appreciation of the types of tissue injury (see Chap. 4) resulting from GERD. The use of the fiberoptic instruments has greatly increased our ability to diagnose the posterior laryngitis of GERD. With clues from the history and the questionnaire, physical examination, pulmonary functions, and direct laryngoscopy, the clinician is usually able to achieve a strong clinical impression that GERD is contributing to the patient’s airway disease. This usually leads to a treatment plan that includes treatment for

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airway inflammation in addition to treatment of GERD. In the geriatric patient this association of GERD and airway disease is often missed. When this group of patients are seen, they are eager for some relief. In my experience, the best results are obtained with effective therapy of both the GERD and airway disease simultaneously. Caution is needed to avoid bronchodilators and other medications that may aggravate GERD (see Chap. 7). Relief of symptoms is more important to the patient than having full documentation of the extent of GERD. Once relief is achieved, the patient is generally more willing and able to cooperate with plans for further studies. A.

Pathophysiologic Changes with Advanced Age

Sensory Changes

As we age, many physiologic processes slowly, almost imperceptibly, change. Change occurs in many aspects of the swallowing process. The higher incidence of aspiration pneumonia in the elderly has been a stimulus for many of the studies that follow. Sensation in the upper airway decreases with age (6–10). While studying the increased incidence of aspiration pneumonia in the elderly, Aviv et al. studied sensory changes in the pharynx and supraglottic area. Using an air pulse pressure stimulus for testing the mucosa enervated by the superior laryngeal nerve (10,11), they demonstrated a decade-by-decade decrease in supraglottic and pharyngeal sensory discrimination threshold (8) (Table 2). Their study of two-point sensory discrimination in the mouth demonstrated an age-related decrease in the floor of the mouth and dorsal and ventral surface of the tongue, but not in the tip of the tongue (7). Calhoun et al. found that the lip had a decrease in tactile and vibratory sensation, the oral cavity had a slight decrease in proprioceptive and temperature sensation, and oral stereognostic ability declined for some shapes but not others (6). This change in stereognostic ability had been previously reported (9,11). These stereognostic skills are similar to those needed to estimate bolus size and may in part account for the larger bolus size swallowed by the elderly (11). Anatomic Changes

Changes in the structure of nerves have been documented with aging. Electronmicroscopic evaluation of age-related changes in postmortem human superior laryngeal nerve segments was performed by Mortelliti et al. (12). They compared tissue from young subjects (age 20–30 years) with tissue from old subjects (age 60–89, mean age of 76.2 years). There was a 31% decrease in number of myelinated nerve fiber counts in the older subjects, which was statistically significant ( p ⫽ 0.032) (12). In addition, the small myelinated fiber group in the elderly

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Table 2 Supraglottic and Pharyngeal Sensory Discrimination Thresholds by Decade Age (yr) 20–30 31–40 41–50 51–60 Mean (20–60) 61–70 71–80 81–90 Mean (61⫹) Total

Mean ⫾ SD (mmHg)

N

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

11 17 7 2

2.06 2.08 2.08 2.70 2.11 2.61 2.49 3.16 2.68 2.30

0.29 0.12 0.13 0.48 0.24 0.49 0.28 1.15 0.63* 0.50

8 7 4 56

* p ⬍ 0.001. Source: Ref. 8.

had decreased 67% ( p ⫽ 0.014). These findings are important to the consideration of other changes of aging as it affects both GERD and its relationships to airway disease in the elderly. Most nerves supplying fibers to the gastrointestinal and respiratory tract have not been studied to this extent. However, it is reasonable to assume that similar changes occur in these nerves that account for some of the other findings to be described. Reflex Changes And Aspiration

Reflex closure of the glottis was studied by Pontoppidan and Beecher in 1960 (13). Using the volume of 1.6% ammonia gas required to stimulate reflex glottic closure, they found that the threshold level increased sixfold from the second to the eighth or ninth decades of life (13). Changes in this glottic closure reflex coupled with decreased sensation make aspiration of even normal secretions more likely in the elderly. This is important, since aspiration of nasopharyngeal secretions occurs in normal individuals. This aspiration has been demonstrated in about 50% of normals, using radioisotopes instilled into the nasopharynx during sleep (14,15). Upper airway aspiration occurring in normal young subjects has significantly greater implications for the elderly. Those elderly at greatest risk for aspiration are those who have had a stroke. There is a 20% incidence of death from aspiration pneumonia in the first year after a stroke, with additional deaths from aspiration pneumonia each year thereafter (16). A careful assessment of the stroke patient is essential to find evidence of sensory or motor dysphagia, which could

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lead to aspiration and pneumonia. This is even more important in the patient with preexistent airway disease. With a stroke, questions arise about whether or not new respiratory symptoms are due to aspiration or an exacerbation of the preexistent disease. A new approach to this assessment includes a combined laryngopharyngeal sensory test and modified barium swallow. This combined approach appears to have a better ability to prognosticate the risks of aspiration, which leads to strategies to avoid the problem (17,18). Other investigators have demonstrated the usefulness of videofluoroscopy with or without the videoendoscopic swallow study in assessing dysphagia in the stroke patient (19,20). These same tools are at times helpful in evaluating the nonstroke patient with GERD and airway disease. Additional reflex changes are described in the next section. Changes in Swallowing

Investigators have found a statistically significant increase in the threshold bolus volume of the pharyngeal swallow in the elderly (21–23). A delay in initiation of maximal hyolaryngeal excursion was the factor responsible for the significantly longer duration of oropharyngeal swallowing in patients over age 70 (24). Nondeglutitive lingual pressure is significantly lower in the elderly (25). Most studies have found that aging results in a significant decrease in resting upper esophageal sphincter (UES) pressure (21,25–27). The UES opening occurs earlier ( p ⫽ 0.01), and the UES opening is significantly diminished ( p ⫽ 0.0001) in the elderly (27,28). There is delayed UES relaxation and prolonged oral transit time (20,21). These factors result in increased hypopharyngeal intrabolus pressure (25,27,28). The net effect of these changes is that flow rates across the UES are unchanged with age. Although the compliance of the UES decreases with age, the increase in bolus pressure helps to compensate. It appears that these changes do not influence normal pharyngo-sphincteric coordination (27). The amplitude of the hypopharyngeal pressure wave varies in the elderly depending on what is swallowed. The amplitude is the same in the young and the elderly for mashed potato; however, with dry or water swallowing the amplitude was significantly greater in the elderly (25). The term presbyesophagus evolved in the 1960s. It referred to certain patterns of esophageal dysfunction. Some of the early studies of patients in their eighth or ninth decades suggested that tertiary contractions, decreased primary peristalsis, decreased LES relaxation, delayed emptying of the esophagus, and dilatation of the esophagus were part of the normal aging process (29,30). More recent studies, using improved intraluminal manometry and better selection of patients to exclude other diseases (such as diabetes mellitus) that may effect esophageal motility, have changed our understanding of what is expected in the elderly. In one study there was a significant decrease in the amplitude of the peristaltic pressure wave in men over 80 years of age (31). Richter et al. found

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that the distal esophageal peristaltic wave amplitude was significantly higher with each increasing decade and peaked in the fifties (32). Severe motility disorders (presbyesophagus) in the elderly have not been found in recent studies. It is believed that the severe motility disturbances found at times in the elderly are caused by systemic diseases rather than the aging process (33,34). Airway-Protective Mechanisms

There are two types of protective mechanisms: those preventing antegrade aspiration and those preventing retrograde aspiration. Retrograde transit includes gastroesophageal and esophagopharyngeal reflux, regurgitation, and vomiting. Airway-protective mechanisms for retrograde aspiration have been divided further into two subgroups (23,24). The first subgroup includes basal mechanisms that are active at all times. The second includes response mechanisms that become active with stimulation. Of the basal mechanisms, the LES presents the first line of defense against GER. Many of the preceding authors have reviewed the problems that permit physiologic and pathologic reflux through the lower esophageal sphincter (LES). The UES provides a high-pressure zone separating the esophagus and pharynx; however, its resting pressure decreases during sleep and with aging (21). This may enhance risks for aspiration in the elderly, particularly during sleep. Response mechanisms often include vagally mediated reflexes, such as the esophago-UES contractile reflex and esophagoglottal closure reflex. The esophagoglottal closure reflex is elicited when mechanical stretching of the esophagus occurs with abrupt distention from refluxate. The reflex results in adduction of the vocal cords. While this reflex is evoked with spontaneous reflux, it may be absent in about half of those over 70 years old (23,35). Esophageal peristalsis is classified into primary, induced by swallowing, and secondary, initiated by local esophageal stimuli. Recent studies of the effect of aging on secondary peristalsis indicated that ‘‘in the healthy elderly volunteers, secondary peristalsis is either absent or its stimulation is inconsistent and significantly less frequent compared with young volunteers’’ (23). For prevention of antegrade aspiration, swallowing is examined in more detail. The swallow is divided into the primary swallow, which is usually a voluntary act, and the secondary swallow, which involves a stimulus applied to the pharynx. The elderly, as mentioned before, require a significantly larger volume of liquid to trigger the secondary (pharyngeal) swallow (21–23). This could permit smaller volumes from the nasopharynx (14,15) or from gastric refluxate to be more easily aspirated. However, it has been suggested that the secondary swallow may help prevent aspiration by activating the swallow-induced glottal closure or at least clear the pharynx of refluxate (23). Injection of minute amounts of water into the pharynx stimulated the pharyngo-glottal adduction reflex with brief

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closure of the vocal cords (35,36). More recent evidence suggests that in the elderly a larger volume of liquid is needed to trigger this reflex (23,35). This implies that smaller volumes of liquid—antegrade or retrograde—would present a greater risk for aspiration. Summary of Pathophysiologic Changes

With progressive aging there occurs loss of upper airway sensation, diminished protective reflexes, changes in swallowing, decreased airway protective mechanisms effecting laryngeal closure, and changes in voice (37). These changes are sometimes found to progress decade by decade, but some changes are only noticed in the seventh, eighth, and ninth decades. These changes appear to place the elderly at far greater risk for aspiration of fluids swallowed or refluxed. These changes of aging may then have serious implications in diagnosis and treatment of GERD and airway disease in the elderly, and they may explain why GERD and airway disease is more difficult to treat in this age group. While some have suggested that gastric acidity declines with age, Hurwitz et al. (38) indicate that 90% of elderly people were able to acidify gastric contents. This finding included the basal unstimulated state. Certainly this combination of findings increases the risk of aspiration pneumonia and other airway diseases (Chaps. 5–8, 12) in the elderly. One example of these differences, as seen in Figure 1 (39), is the fact the GERD moves from the third most common cause of chronic cough in patients of all ages (see Chap. 5) to the second most common cause in the elderly. B.

Evaluation of GERD in the Elderly

There are some unique aspects of evaluating GERD in the elderly. Sometimes the concomitant airway disease and/or additional medical problems (cardiac and orthopedic) prevent the clinician from obtaining the study he or she believes would be most helpful. Often the patient is not willing to go through invasive procedures. The evaluation of GERD has already been thoroughly reviewed (Chaps. 3, 4). Special evaluation techniques are sometimes needed in this group of patients, particularly when aspiration is suspected. Because of the pathophysiologic changes of aging and the possibility of other concomitant disorders (34) and occult stroke (17,18,40), videofluoroscopy carefully performed, using materials of differing consistencies, can be quite rewarding. It helps in identifying abnormal swallowing patterns and upper airway aspiration, as well as GERD with possible aspiration (19,41). The additional use of the laryngoscope can be invaluable in identifying changes of posterior laryngitis characteristic of GERD (Chap. 4) and assessing sensory function (9,17). The laryngoscope can also be used in combination with barium studies or videofluoroscopy to enhance accuracy (18,20,42). In the elderly you may diagnose GERD-associated airway disease, but if you have not considered the possibility of other disorders leading to aspira-

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Figure 1 Causes of chronic cough in the elderly. (a) The cause was determined in 100% of patients; it was due to a single condition in 73% and multiple disorders in 27%. (b) The spectrum and frequency of the 40 causes. PND, postnasal drip syndrome; GER, gastroesophageal reflux; misc, miscellaneous.

tion, you may never achieve a successful treatment plan. When reflux symptoms have been present in this age group, it is extremely important to have an endoscopic exam to look for Barrett’s esophagus (see Chaps. 3 and 6). Studies of elderly patients suggest that they have more severe findings of GERD. Zhu et al. (43) studied 24 elderly patients with a mean age of 69 years (range 65–76) and compared them to 147 younger patients with a mean age of 45 years (range 21–64). Their studies using 24-hour pH monitoring and endoscopy demonstrated that the elderly patients had a higher incidence of pathologic reflux and reflux esophagitis (43). Their elderly patients had a pH ⬍ 4 for 32.5% of the time in 24 hours compared to 12.9% of the time in younger patients ( p ⬍ 0.05). On endoscopy they found that the elderly had more severe esophageal lesions and a greater incidence of hiatal hernia ( p ⬍ 0.002). The elderly had 20.8% incidence of grade III/IV esophagitis versus 3.4% in the younger patients (43). These are all findings that might be expected with the prolonged and progressive disease described in Chapter 9. Collen et al. (44) prospectively studied 228 consecutive symptomatic patients with GERD. Of these patients, 162 were less than 60 years old, and 66 patients were over 60 years old. All patients were evaluated

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for basal acid output and had endoscopic evaluations. There was a much higher incidence of mucosal disease (erosive esophagitis and Barrett’s esophagus) in patients complaining of pyrosis who were elderly (81%) versus (47%) those who were younger ( p ⫽ 0.000002, Fisher’s exact test) (44). This difference in incidence of mucosal disease increased decade by decade from below 30 years to over 70 years, while there were no corresponding differences in basal acid outputs (38,44). These studies taken together point to more severe mucosal disease in the elderly. They suggest there is an increase in acid-contact time and resultant damage to the mucosa. There may also be increased susceptibility to mucosal injury from decreased buffering of acid and decreased effective clearance of refluxate (23,25,43). C.

Treatment

Treatment programs for the elderly are similar, both medically (Chap. 8) and surgically (Chap. 9). The findings that the elderly have more severe disease (43,44) suggest the need for more aggressive therapy (44,45). One-third of the elderly patients studied by Collen et al. (44) required more than 600 mg of ranitidine per day for control of symptoms and healing of esophagitis. This finding and more severe disease in the elderly indicate that early use of proton pump inhibitors may be the most cost-effective therapeutic modality for initial treatment of this age group. As seen in other chapters (4,5,7,8), the proton pump inhibitors have been the most effective medical therapy for GERD and concomitant airway disease. It is not unusual with more severe disease to need combination therapy with a motility agent such as cisapride. In the elderly there is an increase of coincident diseases or conditions that may limit the medications that can be used. This includes the increasing incidence of lactose intolerance with age, which leads to diarrhea with some products (omeprazole) (46). Sicca syndromes may also make the use of proton pump inhibitors more difficult to tolerate (47). The elderly are more prone to develop neurologic sequelae, especially movement disorders, from the use of metoclopramide. The elderly often have greater problems with side effects of medications and difficulties with multiple drug interactions. This is particularly important with the use of cisapride and the cytochrome p450 drug interactions (46). There is a significant list of drugs that can lead to torsade de pointes arrhythmias. Once an effective treatment plan is established, the patient will have questions about cost, safety, and duration of therapy. Cost can be a major factor in all age groups, but elderly patients are often living on fixed incomes and may not have insurance with prescription coverage. Table 3 shows the recent average retail costs of medications, including generics (when available), in one local market. It is apparent that GERD is an expensive disease (47,48). When combined with medications to treat airway

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Table 3 Daily Cost of Therapy Drug Cimetidine generic Ranitidine generic Famotidine Nizatidine Omeprazole Lansoprazole Cisapride Sucralfate generic

Dose 800 800 150 150 20 150 20 30 20 1 1

mg bid mg bid mg bid mg bid mg bid mg bid mg daily mg daily mg bid g qid g qid

Average cost per day $5.48 $2.04 $2.98 $1.87 $3.08 $3.10 $3.44 $3.28 $2.87 $2.89 $2.05

Cost calculations are based on the average retail price of 100 tablets in the Palm Beach County area, December 1997.

disease, the combined cost can be overwhelming. It may force some patients into health maintenance organization insurance coverage just to obtain coverage for the cost of medications. Failure of medical treatment to control either GERD or GERD-induced respiratory disease is a reason for surgical intervention. Some patients will not follow lifestyle changes (particularly weight loss) and/or the long-term costs of medical therapy are unacceptable. These factors can also lead to a rational choice regarding surgical intervention. With newer laporoscopic approaches (see Chap. 9), patients who would not have been considered surgical candidates in the past are now acceptable for surgery. Just as the adjustment of the medication program for GERD can be difficult, so the decision for surgery and type of procedure can be difficult. The clinician must have a surgeon with appropriate skills for fundoplication. Sometimes this means referral to a surgeon out of the immediate area. One of the biggest mistakes in the elderly patient can be procrastination about the decision for surgery. If the patient is suffering from severe respiratory problems because of GERD, appropriate medical and surgical therapy will be needed. Aspiration from GERD will cause progressive fibrosis. Waiting until the patient requires continuous oxygen is a mistake. Sometimes the patient is responsible for the delay in treatment; the physician who has read this far should realize the appropriate time and place for surgical intervention. With the population in this country living longer, we must constantly reassess the question: How old is too old for surgery for GERD?

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Pregnancy is frequently accompanied by heartburn. Baron et al. (50) thoroughly reviewed the literature on GERD in pregnancy. While heartburn is present in 30–80% of pregnancies, it is usually most troublesome during the third trimester (50). The same precipitating factors will be problems in pregnancy as they are in other patients with GERD (see Chap. 8). Smoking and alcohol intake should be avoided during pregnancy for the benefit of the fetus as well as to avoid precipitating GERD. Therapy for GERD during pregnancy is approached with caution because of concerns about teratogenicity of any drug used. Consequently, in this group of patients lifestyle changes are an extremely important first step (see Chap. 8). Antacids have been used by 35% of patients in some populations during third trimester pregnancies (57). Antacids (other than sodium bicarbonate) or alginic acid are usually the drugs of first choice. Sucralfate has been described as apparently safe and has proven effective in a randomized controlled study during pregnancy (50). For the more difficult-to-control GERD of pregnancy, it appears that ranitidine (51) at a dose of 150 mg twice daily is effective. An additional study found no adverse side effects of this class of drugs taken at any time during pregnancy (52). The H 2-blockers are listed as pregnancy category B drugs, while cisapride and omeprazole are category C (46). Lansoprazole is a pregnancy category B drug, but studies of its use in pregnancy have yet to be published. The benefits and risks of therapy are always most closely weighed during pregnancy, and the safest, most effective drug is always preferred. Clearly this is a subject requiring future research.

III. State of the Art While the first descriptions of GERD and airway disease date back to the twelfth century (see Chap. 6), it has taken a long time to gather enough scientific evidence to have this relationship enter the mainstream of medical education. In 1996, the First Multi-Disciplinary International Symposium on Supraesophageal Complications of Reflux Disease was held in Tucson, Arizona. The proceedings of this symposium were published in December 1997 (53). It was also a milestone when in 1997 a textbook was published on asthma with passages dedicated to the relationships between GERD and asthma (54). Unfortunately, in that large textbook no chapter was devoted to GERD and asthma. Still, this was a major advance in the recognition that GERD does influence airway disease, and seven authors in the textbook at least devoted space to point out these relationships.

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A. Evolution of the Human Larynx

Going beyond the embryological development of our aerodigestive system (Chap. 1), comparative and developmental anatomy studies of primates have shown the evolution of the human aerodigestive system (55,56). The descent of the larynx into the neck has resulted in the ability to speak, while losing the more complete separation of the respiratory and digestive systems seen in our closest relatives, nonhuman primates (57). As the human embryo and infant develop, we witness the evolution of this descent of the larynx into the neck (see Chaps. 1,11). B. GERD and Inflammation

In Chapter 2, we have an excellent detailed review of inflammation in asthma. It details the role of the vagus nerve and both the cholinergic and nonadrenergic, noncholinergic nerves in providing reflex changes and inflammation as explanations for part of the mechanism by which GERD causes airway disease. Sanico et al. (58) demonstrated capsaicin-sensitive nerves stimulating neurogenic inflammation in the human upper airway of patients with allergic rhinitis. It is anticipated that reflex nasal inflammation of this type may play a role in some types of rhinitis (59) and sinusitis associated with GERD (Chaps. 4,10,11). Rolla et al. (60) noted that patients with sinusitis have pharyngeal biopsies demonstrating a thinning of the epithelium and increase in density of submucosal nerve fibers. Their study suggests that in nonasthmatics with sinusitis, pharyngeal mucosal changes lead to increased access of irritants to submucosal nerve endings. These changes in the pharyngeal mucosa are associated with an increase in extrathoracic airway responsiveness to histamine and, in some cases, activation of a pharyngobronchial reflex with wheezing. The investigators infer that the mucosal changes are due to chronic postnasal drip of mediators and inflammatory cells from the affected sinuses. Their study did not look for evidence of GERD. It would be easy to infer that this mucosal injury could be a result of reflux into the upper airway. There appears to be evidence for a subgroup of patients with severe sinusitis (61) in whom treatment of GERD can significantly improve the sinusitis, thereby avoiding the need for surgery (62,63). This is an area in need of additional research since confirmation of such a relationship could lead to a major change in the approach to treating severe chronic sinus disease. C. Diagnostic Approaches to GERD and Airway Diseases

The approaches to diagnosis of GERD were reviewed in detail in Chapter 3. However, in Chapter 4, evidence was discussed that patients with reflux laryngitis differ in their findings from patients with symptomatic esophagitis. It appears that studies directed at diagnosing esophagitis (endoscopy and biopsy) and use

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of a single pH probe in the lower esophagus may mislead the investigator. The importance of using a dual pH probe is stressed, as well as the fact that proximal reflux may not show up on a single study. It may be intermittent but frequent enough to cause persistent damage to the sensitive tissues of the upper airway, which are not able to protect against the damage from acid and pepsin. The specificity of the proximal pH probe is excellent (91%), but the sensitivity and reproducibility is only 55% (64,65). This suggests that a single negative test does not exclude proximal reflux as a cause of upper or lower airway disease. Some studies have suggested very high rates of positive proximal pH studies (Chap. 4) (66). Other investigators have suggested a more invasive approach using simultaneous tracheal and esophageal pH probes as a means of detecting microaspiration (67). Ruth et al. (68) are the latest to find a role for scintigraphic detection of aspiration in patients with GERD. This technique has met with mixed results in other studies (see Chap. 7), but some modifications may make it helpful in the pediatric population (69). The patient’s age and state of health will often dictate which diagnostic approach is most appropriate (Chaps. 3–13). D.

Prevalence of GERD in Airway Disease and Airway Disease in GERD

In spite of the high prevalence of GERD in asthmatics (60–80% in adults and 50–60% in children) (Chap. 6), one of the most important deficiencies of studies reported to date has been small numbers of patients studied (Chaps. 6,8,10). While we would all like to see a large prospective study, this would be very expensive and take many years to complete. An interesting study appeared in 1997, with a large retrospective review of the comorbid occurrence of laryngeal or pulmonary disease with esophagitis (70). This research starts with patients who have severe esophagitis or stricture and looks at the prevalence of airway diseases. In 1970, the hospital records of 172 Veterans Affairs (VA) hospitals became computerized. These files are managed by the VA Central Automation Center. Since 1981, the ICD 9 coding has been used for discharge diagnoses. The study group included all patients discharged between 1981 and 1994 who had a primary or secondary diagnosis of GERD-related esophagitis (ICD 9 code 530.1) or esophageal stricture (ICD 9 code 530.3). This group consisted of 101,366 patients. They were compared to an identical number of unmatched control patients selected randomly from the remaining files. These populations were then compared looking at associated medical conditions considered to be extraesophageal manifestations of GERD. There was a significant difference in comorbity for sinusitis, pharyngitis, laryngeal stenosis, chronic bronchitis, bronchial asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, bronchiectasis, pulmonary collapse, and pneumonia ( p ⬍ 0.0001) (70). Sinusitis was the most frequent upper airway problem. Odds ratios showed a strong association

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between laryngitis and laryngeal stenosis and esophagitis (70). Asthma and pulmonary fibrosis had the highest odds ratios for association with esophagitis or stricture (70). This study shows an increased risk or a variety of extraesophageal manifestations of GERD in the study population. Because of the severity of GERD required to be in the study, it may underestimate the risk for extraesophageal manifestations of GERD. Certainly this study will have its critics, but it is unlikely that another study of this size will appear. It helps to point out the clinical significance between GERD and a variety of airway diseases. E. An Office Approach to GERD and Airway Disease

It is important to have a good clinical approach to the diagnosis of GERD (Chaps. 3,4) and a high level of suspicion for the diagnosis of GERD-associated airway diseases (3–12). Keeping in mind that some conditions like cough, reflux laryngitis, and asthma may have silent GERD, the use of a questionnaire, as seen in Table 1, may provide the clinician with a tool to raise levels of suspicion. Beyond a good history, the routine physical exam offers only a few clues (abnormal breath sounds) most of the time. The extension of the examination to include direct fiberoptic laryngoscopy, as described in Chapter 4, is often most rewarding. Pulmonary function testing will help detect obstructive and restrictive components of airway disease. The addition of a flow volume loop will help find those cases of extrathoracic obstruction. This finding helps identify those patients with vocal cord dysfunction syndrome (71,72), a condition that has been associated with GERD (73). Two additional cases, evaluated at the National Jewish Center for Immunology and Respiratory Medicine, are followed in my practice; both have responded well to treatment of GERD and speech therapy. Failure to diagnose vocal cord dysfunction syndrome can have serious consequences for the patient (71), who is frequently treated with high-dose steroids for suspected asthma. Therapeutic trials of therapy for GERD can often be helpful in leading to the diagnosis, but this therapeutic trial must involve sufficient amounts of proton pump inhibitors and an adequate period of treatment, which differs significantly for conditions such as asthma (see Chaps. 7,8) or laryngitis (see Chap. 4). This choice of drugs for therapeutic trial is also affected by age (see Chaps. 10,11) and pregnancy. It is important for each clinician to have confidence in his ability to refer this patient to an appropriate gastroenterologist or otolaryngologist for further evaluation of the underlying GERD-induced problem, especially one familiar with the importance of the dual pH probe study. The next most important decision is when to consider the surgical option. This is an extremely important decision in all age groups (see Chaps. 8–11 and 13). Multiple factors must be considered here, including severity of respiratory disease, rate of progression of respiratory disease, occupation, costs of long-term medical therapy, adequacy of relief of symptoms with maximum medical therapy, availability of a surgeon

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skilled in laparoscopic fundoplication, and whether the patient has an esophageal motility disorder (see Chap. 9). Consideration should also be given to the stages of the progressive damage to the esophagus from bile salts, as described in Chapter 9. So far, long-term studies have suggested that surgery is superior to medical therapy (see Chaps. 7–9). This is another area where we await further research comparing long-term use of high-dose proton pump inhibitors versus long-term follow-up of (laparoscopic or open) fundoplications.

IV. Conclusions Since this book was written for clinicians, it did not cover the large amount of information available on the normal physiology of swallowing (e.g., the complex interactions of the tongue, pharynx, hypopharynx, UES, esophagus, and LES). This information has been addressed in a recent publication (74), and additional information was presented at the First Multi-Disciplinary International Symposium on Supraesophageal Complications of Reflux Disease, November 21–23, 1996. These proceedings were published in 1997 (62). In this book, each contributing author has attempted to present the latest information to help the clinician understand the complex relationships between GERD and airway disease, including approaches to diagnosis and treatment. The large amount of published material referenced and the number of articles in various stages of preparation for print attest to the importance of these relationships in various fields of medical research. It is anticipated that research will continue to confirm additional relationships between GERD and both upper and lower airway diseases (63,75). The development of a new assay for human pepsin may open some new avenues for evaluating the distribution of supraesophageal refluxate (J. A. Koufman, personal communication). There are studies in progress further evaluating the use of cisapride alone in treatment of GERD-induced asthma. Additional proton pump inhibitors and motility agents are in various states of research or near final approval for release in this country. Early evidence suggests that new therapeutic agents may be available to modulate some mediators of neurogenic inflamation (76). The future looks bright for the progressive increase in our armamentarium of treatment modalities and expansion of our knowledge of the relationships between GERD and airway diseases (77).

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AUTHOR INDEX

Italic numbers give the page on which the complete reference is cited.

A Abbott, WO, 69, 87 Abdulian, JD, 311, 312, 321 Abelli, L, 37, 51 Abrahamsson, H, 274, 282 Abrams, JS, 21, 43 Abramson, SJ, 276, 284 Abucan, A, 255, 266 Ackroyd, R, 214, 234 Adami, B, 187, 205 Adams, GK, 23, 43 Adams, PF, 246, 263 Adcock, IM, 31, 48 Addis, A, 187, 205 Adeleine, P, 20, 24, 41, 170, 171, 172, 173, 178, 196, 198, 207 Advenier, C, 30, 31, 33, 47, 48, 49 Agee, J, 26, 45 Ahlstedt, S, 20, 21, 42 Ahmad, M, 180, 181, 203 Akers, S, 89, 90, 103, 107 Alam, R, 19, 23, 40 Albanese, C, 279, 284 Albertucci, M, 99, 111, 225, 227, 228, 230, 236 Alexander, RW, 20, 41, 104, 112, 146,

147, 148, 157, 158, 170, 172, 174, 178, 250, 256, 257, 265 Alger, L, 28, 46 Alland, S, 243, 263 Allen, CJ, 90, 95, 96, 99, 103, 104, 105, 106, 107, 110 Allen, F, 274, 282 Allen, FW, 247, 263 Allen, ML, 103, 112 Allen, TGJ, 37, 52 Aloe, L, 33, 49 Altemus, JB, 37, 38, 51 Altorki, NK, 161, 175 Altschuler, SM, 95, 105, 110, 274, 282 Amberg, JR, 308, 320 Ambrecht, U, 255, 266 Amemiya, T, 33, 49, 90, 107 Ament, ME, 60, 67, 90, 92, 99, 108, 129, 130, 138, 244, 247, 259, 263, 267, 274, 279, 281, 284 Amodio, JB, 276, 284 Amoury, RA, 276, 284 Amyot, R, 168, 177, 183, 205 Andersen, C, 33, 49 Andersen, LI, 20, 41, 95, 109, 143, 158, 173 Anderson, JA, 20, 41

323

324

Author Index

Anderson, P, 28, 31, 39, 46 Andersson, KE, 131, 138, 165, 167, 177 Ando, MI, 28, 29, 46 Andreotti, MR, 275, 283 Andze, GO, 129, 130, 138 Angelides, A, 272, 281 Angelucci, F, 33, 49 Anggard, A, 37, 51 Ansaldi, N, 285, 300 Arakawa, M, 90, 93, 108 Arana, J, 105, 113 Arciniega-Oliver, RM, 104, 112 Arenberg, B, 77, 87 Arguelles-Martin, F, 251, 258, 265, 267 Arndorfer, R, 244, 263, 270, 280 Aronow, E, 272, 281 Ashcraft, E, 244, 263 Ashcraft, KW, 276, 284 Asher, MI, 244, 263 Ashraf, MM, 152, 174 Assoufi, B, 20, 21, 24, 42, 44 Atsuta, S, 315, 321 Aubert, A, 224, 228, 230, 235, 260, 267 Aubier, M, 247, 263, 265 Auricchio, S, 270, 280 Austin, J, 168, 177, 183, 204, 274, 282 Averill, DB, 77, 87 Avert, ME, 253, 266 Aviv, JE, 306, 308, 310, 319 Avner, D, 189, 192, 206 Aye, R, 225, 236 Ayers, JG, 179, 197, 203 Aziz, Q, 310, 321 Azizkhan, RG, 258, 267 Azzar, D, 20, 24, 41, 170, 171, 172, 173, 178, 196, 198, 207

B Badalamenti, S, 105, 113, 185, 205 Badier, M, 105, 113, 125, 126, 137 Bafrett, J, 65, 68 Bagley, CJ, 19, 23, 40 Bai, TR, 31, 48

Bailey, B, 187, 205 Bain, WM, 70, 78, 85, 241, 242, 243, 262 Baker, DG, 38, 52 Baker, J, 28, 46 Baker, LA, 99, 111 Bakewell, M, 270, 279 Balaban, DH, 161, 162, 163, 164, 169, 175, 247, 263 Ballantine, T, 275, 279, 283, 284 Ballard, RD, 144, 158, 174, 248, 265 Balocco, P, 285, 300 Balson, B, 251, 252, 256, 257, 265 Baltazan, MH, 257, 267 Baluk, P, 26, 28, 31, 39, 45, 46 Bannister, WK, 152, 174 Baraniuk, JN, 30, 33, 34, 48, 49 Barbara, L, 254, 266 Barbero, GJ, 318, 322 Bardelli, E, 94, 95, 109 Bardham, KD, 56, 60, 67 Baredes, S, 310, 321 Barkans, J, 21, 24, 43, 44 Barneon, G, 20, 21, 41 Barnert, J, 168, 177 Barnes, BE, 270, 280 Barnes, P, 248, 265 Barnes, PJ, 20, 22, 25, 26, 28, 30, 31, 33, 34, 37, 38, 39, 41, 42, 46, 47, 48, 49, 51, 52, 314, 321 Barnett, C, 271, 280 Baron, TH, 314, 321 Barradell, LB, 189, 192, 206 Barrison, GM, 275, 283 Bartelsman, JF, 104, 112, 192, 194, 206, 257, 267 Barter, CE, 161, 162, 169, 176 Barthlow, HG, 22, 28, 31, 39, 43 Bartolotti, M, 270, 280 Bartter, T, 89, 90, 103, 107 Barudi, C, 129, 130, 138, 184, 205 Barundi, C, 240, 261 Bastian, RW, 308, 310, 319 Batch, AJ, 90, 108 Battaglia, G, 105, 113

Author Index Bauer, FE, 37, 52 Bauman, N, 274, 282 Bauman, NM, 77, 87 Baumgarten, CR, 23, 31, 42 Beasley, CRW, 20, 21, 41 Beatty, TW, 70, 78, 86 Beaudy, PH, 244, 263 Becker, DJ, 103, 112, 183, 184, 204, 205 Beckett, HA, 285, 300 Beecher, HK, 307, 319 Behar, J, 105, 113, 189, 192, 206 Bel, A, 90, 107, 123, 124, 137 Beland, J, 37, 51 Belenky, WM, 240, 262 Bellamy, JF, 30, 31, 47 Belmont, JR, 240, 241, 261, 275, 283 Belsey, R, 117, 136, 224, 228, 230, 235 Belvisi, M, 37, 38, 51, 52 Bendig, DW, 275, 283 Bengtsson, U, 155, 175, 316, 322 Benini, S, 94, 95, 109 Benjamin, SB, 83, 88, 92, 93, 108, 109, 241, 242, 262, 270, 279 Bennett, FM, 20, 41, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 103, 107 Bennett, JR, 103, 112, 180, 184, 203, 205, 260, 267 Bensoussan, AL, 224, 228, 230, 235 Bentley, AM, 20, 21, 24, 42, 43, 44 Berant, M, 273, 281 Berdon, WE, 276, 284 Berenberg, W, 69, 80, 87 Berenguer, J, 180, 197, 203 Berenson, NN, 189, 192, 206 Berger, K, 183, 204 Berghammer, G, 272, 281 Bergren, A, 186, 188, 205 Berkowtiz, D, 273, 281 Berkson, J, 123, 137 Bermejo, J, 214, 234 Berni Canani, J, 243, 263 Berni Canani, R, 243, 263 Bernsford, RG, 215, 234 Bernstein, A, 24, 44, 186, 188, 205

325 Bernstein, J, 241, 262 Bernstein, LM, 99, 111 Berquist, WE, 24, 44, 119, 129, 130, 131, 136, 138, 165, 177, 183, 204, 247, 263, 274, 281, 282 Berrisford, RG, 156, 157, 175 Berstad, A, 192, 206 Bertrand, C, 28, 31, 46 Bervoets, D, 292, 301 Beste, DJ, 99, 111 Bettagha, G, 185, 205 Bettex, M, 276, 284 Beumont, PJV, 286, 300 Bevenius, J, 287, 300 Beveridge, BR, 214, 234 Biancani, P, 105, 113 Bianchi Porro, G, 311, 313, 321 Bierman, CW, 239, 261 Bittinger, M, 168, 177 Bjornsdottir, US, 20, 22, 23, 42 Bjornsson, E, 285, 300 Blackburn, KS, 93, 109 Blackshaw, LA, 163, 176 Blackwell, JN, 309, 320 Blalock, PD, 70, 71, 76, 86 Blane, Ce, 279, 284 Blaser, K, 24, 44 Blitzer, A, 306, 308, 310, 319 Block, SM, 93, 109 Bloom, BS, 83, 88, 182, 204 Bloom, SR, 37, 52 Bluestone, CD, 242, 262 Blum, AL, 187, 205 Blum, AM, 23, 42 Blum, D, 274, 275, 282 Bochner, BS, 20, 21, 22, 23, 42 Bochnowitz, S, 38, 53 Bocus, P, 254, 266 Bode, E, 24, 44 Boer, L, 24, 44 Bogdasarian, RS, 70, 71, 78, 86 Boichot, E, 33, 49 Boileau, R, 37, 38, 51 Boisen, RJ, 103, 112, 183, 204 Bolio, A, 253, 266

326 Bolser, DC, 31, 48 Boman, G, 285, 300 Bonavina, L, 105, 113, 125, 126, 137, 170, 171, 178, 197, 207, 217, 225, 227, 228, 230, 232, 235, 236 Bondy, GP, 31, 48 Bonini, S, 33, 49 Book, LS, 273, 274, 281 Bordeaux, EA, 73, 87 Borish, L, 21, 43 Bornhofen, B, 255, 266 Bothwell, MR, 318, 322 Bottomicca, F, 315, 322 Boushey, HA, 33, 49, 180, 203 Bousquet, J, 20, 21, 41 Bouzo, MH, 187, 205 Bovo, P, 94, 95, 109 Bowden, JJ, 26, 37, 38, 46, 52, 53 Boyle, JT, 95, 105, 109, 110, 152, 153, 154, 155, 158, 160, 175, 274, 282 Bradding, P, 21, 22, 42 Bradley, B, 24, 44 Bradley, LA, 20, 41, 104, 112, 145, 146, 147, 148, 157, 158, 170, 172, 174, 178, 250, 256, 257, 265 Brady, DA, 310, 312, 320 Brady, JM, 289, 301 Brady, JP, 287, 300 Braillon, G, 20, 24, 41, 119, 137, 170, 171, 172, 173, 178, 196, 198, 207 Braman, SS, 89, 106 Brand, L, 24, 44, 123, 124, 125, 126, 128, 129, 137, 163, 168, 170, 176, 180, 196, 197, 199, 200, 203, 207 Brandstatter, G, 187, 205 Brandt, ML, 129, 130, 138 Brant, R, 124, 137, 160, 169, 170, 175, 180, 203, 285, 300 Braunstein, G, 30, 47 Bray, GW, 116, 136 Bray, PF, 273, 274, 281 Bredt, DS, 37, 39, 51 Bremner, CG, 196, 199, 207, 211, 212, 215, 224, 228, 230, 234, 235, 258, 267 Bremner, RM, 215, 222, 226, 234, 235

Author Index Brenic, S, 104, 112 Breslin, ABX, 90, 92, 93, 94, 95, 96, 98, 99, 107, 109, 243, 263 Bret, P, 90, 108 Bretza, J, 119, 137 Brewer, JP, 21, 43 Britton, WJ, 21, 43 Broaddus, VC, 24, 25, 45 Brodin, E, 34, 50 Brooks, LS, 60, 68 Brown, CM, 286, 300 Brown, CR, 31, 48 Brown, M, 248, 265 Brown, MA, 244, 263 Brown, P, 125, 126, 137, 186, 188, 205 Bruce, AN, 20, 25, 26, 31, 41 Brummer, RJ, 144, 158, 174, 248, 265 Brussino, L, 315, 322 Bruyns, J, 260, 267 Bryant, GH, 161, 175 Bryne, WJ, 253, 266 Brzana, RJ, 98, 101, 110 Bucca, C, 315, 322 Buckner, CK, 22, 28, 31, 39, 43 Bulluck, GR, 23, 42 Bundgaard, A, 20, 41, 95, 109, 143, 158, 173 Bunnett, NW, 26, 46 Burden, DT, 38, 53 Burghard, G, 93, 97, 98, 109, 142, 148, 157, 158, 173, 180, 203 Burke, AJ, 70, 78, 86 Burne, WJ, 60, 67 Burnstock, G, 37, 52 Burrows, B, 21, 43 Busse, WW, 20, 22, 23, 42 Butani, L, 317, 322 Butland, RJ, 104, 112, 192, 193, 194, 206 Buts, JP, 129, 130, 138, 184, 205, 240, 261 Buttery, LDK, 37, 51 Button, B, 274, 282 Byrne, WJ, 90, 92, 99, 108, 129, 130, 138, 244, 253, 263, 266

Author Index

327 C

Cabezas, GA, 38, 53 Cadiere, GB, 260, 267 Cadieux, A, 37, 52 Cadman, D, 244, 263 Cahill, JL, 276, 284 Caletti, GC, 254, 266 Calhoun, J, 257, 267 Calhoun, KH, 306, 319 Calhoun, WJ, 21, 43 Calus, D, 129, 130, 138 Calverley, PMA, 156, 157, 158, 175, 316, 322 Cameron, AJ, 90, 108 Campbell, AM, 161, 162, 169, 176 Campbell, BH, 70, 78, 86 Campbell, M, 244, 263 Campfield, J, 272, 281 Canning, BJ, 22, 28, 30, 31, 34, 35, 37, 38, 39, 42, 47, 50, 52 Carceller-Blanchard, A, 224, 228, 230, 235 Carling, L, 192, 206 Carlsson, S, 155, 175, 316, 322 Carrasco, E, 20, 24, 41, 56, 67, 125, 126, 137, 170, 171, 172, 178, 186, 188, 196, 197, 205, 260, 267, 279, 284 Carre, IJ, 272, 281 Carstairs, JR, 30, 48 Casale, TB, 25, 38, 39, 45 Casimir, G, 243, 263 Castell, DO, 56, 59, 61, 62, 65, 66, 67, 68, 78, 87, 90, 93, 94, 96, 98, 99, 103, 107, 110, 111, 112, 125, 138, 152, 155, 156, 170, 171, 172, 174, 175, 178, 182, 183, 184, 185, 192, 204, 205, 206, 216, 235, 255, 256, 266, 267, 308, 309, 318, 320, 322 Castell, JA, 63, 65, 68, 90, 94, 99, 107, 156, 170, 171, 172, 175, 178, 184, 205, 309, 320 Castell, MS, 308, 320 Cattau, EL, 93, 109

Catto-Smith, A, 274, 282 Caughey, G, 38, 53 Cavallini, G, 94, 95, 109 Cervero, F, 25, 31, 45 Challacombe, SJ, 298, 302, 312, 321 Chan, B, 26, 45 Chandler, JP, 122, 137 Chanez, P, 20, 21, 41 Chang, MH, 275, 283 Chapman, RW, 23, 43 Charette, L, 247, 248, 249, 263 Charpin, D, 105, 113, 125, 126, 137 Chastang, JF, 78, 88 Cheadle, WG, 78, 88, 183, 204 Chejfec, B, 196, 197, 199, 200, 207 Chejfec, G, 20, 24, 40, 44, 125, 126, 128, 129, 137, 163, 168, 170, 176, 180, 196, 198, 203, 207 Chen, MY, 242, 262 Chen, PH, 275, 283 Chen, XR, 33, 49 Chen, YK, 311, 312, 321 Cherian, P, 56, 60, 67 Chernow, B, 90, 93, 107, 125, 138, 155, 156, 175 Cherry, J, 69, 70, 71, 86, 117, 136 Chesrown, SE, 37, 38, 51 Cheung,A, 37, 52 Chinchilli, VM, 180, 203 Chintam, R, 20, 40, 196, 198, 207 Chobanian, SJ, 56, 57, 60, 64, 67 Christensen, J, 167, 177 Christian, EP, 26, 46 Christie, DL, 129, 130, 138, 247, 263, 276, 284 Christofides, ND, 37, 52 Chudry, N, 33, 50 Chung, KF, 28, 46 Church, MK, 21, 22, 42, 43 Ciarleglio, C, 93, 109 Cirillo, B, 243, 263 Clarke, DD, 270, 279 Claus, D, 240, 261 Close, LG, 308, 310, 319 Cloutier, MM, 90, 107, 243, 263 Coben, RM, 93, 109

328 Cobos, A, 272, 274, 280 Coburn, RF, 37, 38, 51 Cochran, W, 75, 87, 241, 262 Coffman, RL, 21, 43 Coghlan, HC, 147, 148, 150, 162, 169, 174 Cognon, C, 31, 48 Cohen, D, 93, 109 Cohen, S, 95, 105, 109, 110, 131, 138, 152, 153, 154, 155, 158, 160, 167, 175, 177, 182, 204, 247, 263, 274, 282 Colagrande, P, 315, 322 Colasurdo, GN, 38, 53 Colebatch, HJH, 152, 174 Coleman, RA, 37, 51 Coleridge, HM, 26, 34, 35, 37, 45, 50, 92, 108 Coleridge, JCG, 26, 34, 35, 37, 45, 50, 92, 108 Collen, MJ, 311, 312, 321 Collier, BD, 316, 322 Collins, KA, 93, 109 Colon, AR, 270, 279 Colton, R, 310, 320 Colton, T, 121, 137 Colturi, T, 69, 70, 71, 72, 79, 86 Conley, SF, 99, 111 Constantini, M, 222, 226, 235 Contencin, P, 70, 75, 80, 86, 239, 240, 241, 253, 261, 315, 321 Cook, I, 270, 280 Cook, IJ, 308, 320 Cooke, HJ, 38, 53 Cooper, DN, 24, 44, 186, 188, 205 Cooper, JB, 66, 68, 69, 71, 72, 87, 96, 110, 156, 175 Coran, AG, 244, 259, 263, 267, 276, 279, 284 Corey, M, 275, 283 Cornu, G, 129, 130, 138, 240, 261 Corrales, R, 97, 110 Corrao, WM, 56, 67, 89, 90, 106, 243, 263 Corrigan, CJ, 20, 21, 23, 24, 42, 43, 44

Author Index Corsello, BF, 20, 41, 143, 145, 148, 157, 158, 173 Corwin, RW, 155, 175 Costa, DL, 26, 46 Coumaros, D, 93, 97, 98, 109, 125, 126, 137, 142, 148, 157, 158, 173, 180, 203 Courtney, JV, 105, 113, 125, 126, 137, 170, 171, 178, 197, 207, 217, 232, 235 Cowan, RJ, 81, 88 Cowie, RL, 124, 137, 160, 169, 170, 175, 180, 203, 285, 300 Crausaz, FM, 155, 175 Craven, MA, 90, 95, 99, 103, 104, 105, 106, 107, 110 Crookes, PF, 222, 226, 235 Cucchiara, S, 270, 275, 280, 283 Cuello, C, 26, 30, 39, 45 Cui, YY, 33, 49 Culebras, A, 162, 176 Cummins, MM, 69, 70, 72, 76, 78, 84, 85 Cunha, FQ, 33, 49 Cunningham, ET, 140, 141, 173 Curley, FJ, 20, 41, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 106, 107, 108, 170, 171, 172, 178, 180, 203, 243, 262 Curran, J, 93, 109 Cuschieri, A, 183, 204, 259, 267

D D’Esopo, W, 244, 263 Dab, I, 105, 113, 275, 283 daCosta, FAM, 37, 51 Dahlqvist, A, 37, 52 Dale, HH, 34, 50 Dalton, CB, 56, 62, 63, 67, 68, 99, 111, 184, 205, 308, 320 Dalton, JF, 306, 319 Damme, JV, 24, 44 Daneman, A, 275, 283

Author Index Daouli, S, 31, 33, 48, 49 Davi, G, 105, 113, 185, 205 Davidson, A, 275, 284 Davidson, GP, 270, 279, 280 Davis, MV, 119, 137 Davis, P, 272, 281 Davis, PB, 161, 176 Davis, PM, 255, 266 Davis, RS, 119, 136, 143, 144, 148, 157, 173, 248, 249, 265, 273, 281 Dawson, D, 56, 60, 67 de Blieck-Hogervorst, JMA, 292, 301 de Caestecker, JS, 96, 110 de la Bellacasa, JP, 272, 274, 280 de Ritis, G, 275, 283 Debell, M, 306, 310, 319 deBlic, Y, 247, 248, 265 DeBruijne, JW, 192, 206 Dechner, WK, 241, 242, 262 Dedon, J, 310, 312, 320 Dees, SC, 248, 265 DeGennaro, FC, 31, 48 Dekkers, CP, 192, 206 DeKruyff, RH, 21, 44 Delagado-Munoz, MD, 239, 261 Delahunty, JE, 70, 71, 85 Delattre, JF, 163, 176 Della Roandi, GM, 243, 263 dellaRocca, A, 270, 280 Delpierre, S, 38, 52 DeLuca, G, 270, 280 DeMeester, TR, 62, 68, 96, 99, 103, 105, 110, 111, 112, 113, 125, 126, 137, 161, 162, 170, 171, 175, 176, 178, 183, 196, 197, 199, 204, 207, 211, 212, 214, 215, 217, 222, 223, 224, 225, 226, 227, 228, 229, 230, 232, 234, 235, 236, 258, 267, 270, 280, 291, 301 Denault, L, 270, 280 Denis, P, 20, 40, 196, 198, 207 Denjean, A, 20, 33, 41, 95, 109, 150, 151, 158, 174, 248, 265 Dennish, DW, 78, 87 Dennish, GW, 183, 204

329 Denoyelle, F, 77, 87 Dent, J, 61, 68, 104, 112, 163, 176, 214, 234, 238, 260, 270, 280, 308, 320 Depla, AC, 104, 112, 192, 194, 206, 257, 267 Derkx, HHF, 253, 266 deRoy, C, 188, 205 Desai, MC, 28, 46 Deschner, WK, 93, 97, 98, 109 Deshazo, RD, 20, 21, 23, 42 DeVault, KR, 61, 68, 99, 103, 111, 182, 185, 204, 205 DeVita, C, 243, 263 Dey, RD, 30, 35, 37, 38, 47, 51, 52 Deynoyelle, F, 70, 80, 86 Di Mario, F, 105, 113 Di Simone, MB, 254, 266 Diamond, B, 306, 308, 310, 319 Diamond, L, 37, 38, 51 Dillard, VL, 271, 280 Dillon, PW, 276, 284 DiLorenzo, C, 270, 280 DiMarino, AJ, 131, 138, 167, 177, 247, 263, 274, 282 DiMario, F, 185, 205 DiMartino, AJ, 93, 109 DiPalma, J, 270, 279 Djukanovic, R, 20, 21, 31, 41, 48 Do Vale, J, 69, 87 Dobhan, R, 62, 68, 216, 235 Dodds, WJ, 73, 79, 87, 156, 175, 238, 244, 260, 263, 270, 280, 291, 301, 308, 309, 320 Doerschuk, CM, 28, 46 Dollery, C, 248, 265 Domeij, S, 37, 52 Don, H, 38, 52 Donnelly, RJ, 156, 157, 175, 215, 234, 316, 322 Donner, MW, 140, 141, 173, 242, 262, 304, 319 Dordal, MT, 257, 267 Dowdeswell, R, 162, 176 Downing, SE, 273, 274, 281

330

Author Index

Drane, WE, 93, 109 Dray, A, 28, 32, 47, 48 Drazen, JM, 31, 37, 38, 39, 48, 51, 53, 180, 203 Dua, KS, 309, 310, 320 Dubois, J, 89, 90, 103, 107 Ducasse, A, 163, 176 Ducolone, A, 93, 97, 98, 109, 125, 126, 137, 142, 148, 157, 158, 173, 180, 203 Dunbar, J, 271, 280 Dunnill, MS, 20, 41 Dupin, B, 105, 113, 125, 126, 137 Duranceau, A, 168, 177, 183, 205 Durham, SR, 20, 21, 24, 42, 43, 44 Durie, P, 275, 283 Duroux, P, 20, 33, 41, 95, 109, 150, 151, 158, 174, 248, 265 DuSouich, P, 168, 177, 183, 205 Dutto, L, 315, 322

E Eappon, S, 28, 46 Earis, JE, 24, 44, 186, 188, 205 Eccles, JD, 288, 290, 292, 301 Edmonds-Alt, X, 31, 33, 48, 49 Egan, RW, 23, 43 Eggli, DF, 307, 309, 319 Eizaguirre, I, 105, 113 Ekberg, O, 308, 310, 319 Ekstrom, F, 248, 265 Ekstrom, P, 192, 206 Ekstrom, T, 95, 109, 144, 158, 162, 165, 166, 170, 171, 172, 174, 176, 177, 178, 186, 187, 188, 205 El-Serag, HB, 316, 322 Elbon, CL, 39, 54 Ellis, JL, 22, 28, 31, 39, 43, 47 Elta, G, 69, 70, 71, 72, 79, 86 Emonds-Alt, X, 30, 31, 47 Enander, I, 20, 21, 41 Ercolini, P, 275, 283 Erzurum, SC, 180, 181, 203 Euler, AR, 60, 67, 90, 92, 99, 108, 129,

130, 138, 244, 253, 263, 266, 279, 284 Evans, CC, 156, 157, 158, 175, 215, 216, 234, 235, 316, 322 Evans, S, 272, 280 Everett, SL, 270, 279

F Fahrenkrug, J, 37, 51 Fajac, I, 30, 47 Fame, TM, 38, 53 Farmer, SG, 22, 33, 43 Farrar, JF, 247, 263, 274, 282 Faulds, D, 189, 192, 206 Favez, G, 155, 175 Federman, Q, 79, 88 Feigelson, J, 275, 283 Fein, M, 211, 228, 234 Feinberg, MJ, 308, 310, 319, 321 Feinstein, AR, 122, 137 Feldman, M, 271, 280 Feldman, W, 244, 263 Fendrick, M, 83, 88, 182, 204 Fenton, BH, 81, 88 Fernandez, X, 23, 43 Ferrari, A, 254, 266 Ferrari, M, 94, 95, 109 Ferriera, SH, 33, 49 Ferriero, J, 241, 262 Ferry, GD, 275, 283 Festen, HP, 192, 206 Festen, HPM, 83, 88 Fett, SL, 56, 67, 180, 197, 203 Field, SK, 124, 137, 160, 169, 170, 175, 180, 203, 285, 300 Filipi, CJ, 223, 229, 235 Filler, SJ, 98, 111, 286, 288, 291, 292, 300, 301 Fischer, A, 26, 30, 33, 34, 35, 37, 38, 39, 45, 47, 49, 50, 51, 52, 53 Fish, JE, 180, 203 Fitzgerald, G, 248, 265 FItzgerald, JM, 90, 99, 103, 104, 106, 107

Author Index Fitzgerald, S, 26, 46 Flament, JB, 163, 176 Flanagan, TL, 26, 45 Flannery, EM, 21, 43 Flores, AF, 273, 281 Foda, HD, 37, 52 Foglia, RP, 105, 113 Folkesson, HG, 24, 25, 45 Follette, D, 279, 284 Fong, T, 31, 48 Fonkalsrud, EW, 24, 44, 90, 92, 99, 105, 108, 113, 244, 259, 263, 267, 276, 279, 284 Fontana, R, 189, 206, 257, 267 Foran, SK, 23, 43 Forbes, DA, 257, 267 Ford, GA, 104, 112, 192, 193, 194, 206 Forge, P, 90, 108 Forget, PP, 105, 112, 189, 206, 247, 263 Forichon, J, 20, 24, 41, 170, 171, 172, 173, 178, 196, 198, 207 Fornes, MF, 56, 67 Forsgren, S, 37, 52 Foster, AC, 275, 283 Foster, LJ, 165, 167, 177 Foster, PS, 23, 43 Fowler, AA, 24, 44 Fox, AJ, 28, 47 Fox, WW, 274, 282 Franco, P, 274, 275, 282 Franconi, G, 38, 53 Franssila, S, 289, 301 Fraser, R, 270, 279 Frazer, A, 247, 263 Freeman, JK, 270, 280 Freeman, SR, 170, 172, 177, 192, 193, 194, 206 Freije, JE, 70, 78, 86 French, CL, 20, 41, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 106, 107, 108, 170, 171, 172, 178, 180, 203 Freston, JW, 99, 111, 182, 204 Friedland, GW, 129, 130, 138 Frieling, T, 38, 53

331 Frisken, K, 286, 300 Frossard, N, 30, 47 Fryer, AD, 22, 39, 42, 53, 54 Fuchs, KH, 99, 111 Fuentes, P, 105, 113, 125, 126, 137 Fuji, K, 28, 29, 46 Fujimori, K, 90, 93, 108 Fujimura, M, 33, 49, 90, 107 Fukuchi, Y, 24, 45 Fukumura, D, 33, 50 Fuller, RW, 30, 48, 103, 112 Fulp, SR, 308, 320 Fumagalli, J, 187, 205 Furkert, J, 23, 31, 42

G Gabb, M, 308, 320 Gacek, RR, 306, 319 Gadmundsson, K, 239, 261 Gall, DG, 257, 267, 275, 283 Gallant, SP, 93, 108, 155, 175 Galleano, E, 285, 300 Galleguillos, F, 20, 24, 41, 56, 67, 125, 126, 137, 170, 171, 172, 178, 186, 188, 196, 197, 205, 260, 267, 279, 284 Galmiche, JP, 187, 205 Gambone, LM, 39, 54 Garabedian, EN, 77, 87 Garay, J, 105, 113 Gardiner, DG, 38, 53 Garland, A, 28, 46 Gastal, OL, 156, 175 Gaston, B, 37, 39, 51 Gaudric, M, 167, 177, 183, 204 Geisinger, KR, 93, 109 Gelder, C, 31, 48 Gelfand, DW, 59, 67, 81, 88 Gentles, MG, 258, 267 Geppetti, P, 28, 31, 46 Gergen, PJ, 246, 263 Gerhardt, DC, 73, 87 Germain, N, 33, 49 German, VG, 97, 110

332 Germonpre, PR, 23, 30, 42, 47 Gervaise, E, 270, 279 Geubelle, F, 90, 108 Ghaed, N, 155, 175 Ghanekar, SV, 22, 28, 31, 39, 43 Ghavanian, N, 20, 21, 41 Ghillebert, G, 98, 99, 101, 110, 111 Giachetti, A, 26, 45 Gibbins, IL, 35, 37, 38, 50, 52, 53 Gibbs, CP, 24, 44 Gibson, B, 306, 319 Gibson, GG, 214, 234 Gibson, WS, 75, 87, 241, 262 Gideon, RM, 90, 107 Gilmour, AG, 285, 300 Girault, F, 275, 283 Giudicelli, R, 105, 113, 125, 126, 137 Glab, N, 95, 109, 140, 142, 148, 157, 173, 273, 281 Glanz, H, 70, 71, 78, 86 Gleeson, K, 307, 309, 319 Gleich, GJ, 21, 43 Glicklich, M, 244, 263 Glock, MS, 70, 80, 86 Godard, P, 20, 21, 42 Gold, WM, 37, 38, 51 Goldberg, AB, 21, 43 Goldberg, H, 79, 88 Goldie, RG, 22, 33, 43 Goldman, AL, 165, 167, 177 Goldman, G, 24, 44, 45 Goldman, JM, 180, 203, 260, 267 Goldstein, BD, 32, 48 Goldsworthy, W, 270, 279 Gomes, H, 253, 266 Gonzalez-Fernandez, F, 251, 258, 265, 267 Good, JT, 24, 44 Goodall, RJ, 24, 44, 186, 188, 205 Goodwin, C, 276, 284 Gooszen, HG, 224, 228, 230, 235 Gormand, F, 20, 24, 41, 119, 137, 170, 171, 172, 173, 178, 196, 198, 207 Gourley, GR, 259, 267 Gower, VC, 240, 262 Gozetti, G, 254, 266

Author Index Grad, R, 240, 262 Graf, PD, 38, 53 Grand, RJ, 256, 266, 275, 283 Grant, AK, 214, 234 Grant, JA, 24, 44 Graves, J, 38, 53 Gray, WR, 97, 110, 307, 309, 319 Greenfield, SM, 298, 302, 312, 321 Greenlee, G, 196, 197, 199, 200, 207 Greenlee, H, 20, 24, 40, 44, 125, 126, 128, 129, 137, 163, 168, 170, 176, 180, 196, 198, 203, 207 Gremillion, DE, 142, 148, 157, 158, 173 Grette, K, 98, 99, 111 Greyson, ND, 155, 175 Grob, JC, 93, 97, 98, 109, 125, 126, 137, 142, 148, 157, 158, 173, 180, 203 Gross, NJ, 33, 34, 49 Grundfast, K, 240, 241, 261, 275, 283 Grunstein, MM, 119, 129, 130, 136, 138, 143, 144, 148, 157, 173, 248, 249, 265, 273, 281, 314, 321 Gudmundsson, K, 291, 292, 301 Guenel, P, 78, 88 Guerre, J, 167, 177, 183, 204 Guiffre, RM, 275, 283 Guivarch, M, 224, 228, 230, 235, 260, 267 Gunasekaren, TS, 256, 258, 267 Gunther, T, 69, 87 Gupta, RR, 103, 112, 183, 204 Gustafsson, PM, 129, 130, 138, 247, 256, 258, 263, 267 Gutierrez, M, 317, 322 Guzzo, MR, 20, 41, 56, 60, 67, 104, 112, 146, 147, 148, 150, 157, 158, 162, 169, 170, 172, 174, 178, 250, 256, 257, 265

H Haber, M, 189, 192, 206 Haberberger, R, 37, 52

Author Index Hagen, JA, 196, 199, 207, 211, 212, 222, 226, 228, 230, 234, 235, 236 Haile, JM, 145, 146, 148, 157, 158, 174 Hall, AE, 31, 48 Hall, AW, 291, 301 Hall, WJ, 90, 103, 107 Halpern, L, 274, 283 Halstead, LA, 318, 322 Ham, H, 260, 267 Hamamoto, J, 28, 29, 46 Hamdy, S, 310, 321 Hameister, HH, 95, 109, 140, 142, 148, 157, 173, 273, 281 Hamid, Q, 20, 21, 42, 43 Hamilton, JW, 103, 112, 183, 204, 308, 309, 320 Hamman, RF, 24, 44 Hammer, B, 96, 110 Hamosh, M, 270, 279 Hanaway, PJ, 243, 263 Hand, CRK, 156, 157, 158, 175 Handy, D, 275, 284 Hansel, TT, 24, 44 Hanson, DG, 70, 71, 72, 78, 81, 83, 86, 87, 88, 104, 112, 240, 261 Harder, RV, 90, 103, 107 Harding, SM, 19, 20, 24, 40, 41, 56, 60, 63, 67, 68, 104, 112, 145, 146, 147, 148, 150, 157, 158, 162, 169, 170, 172, 174, 178, 179, 192, 194, 197, 203, 206, 250, 256, 257, 265, 313, 321 Hardy, KA, 246, 263 Harmon, JW, 94, 109 Harned, HS, 241, 262 Harper, PC, 186, 188, 205 Harrington, JW, 70, 78, 85, 241, 242, 243, 262 Hartley, L, 306, 319 Haslam, R, 270, 279 Hassall, CJS, 37, 52 Hassall, EG, 256, 258, 267, 275, 284 Hathaway, T, 26, 45 Hatlebakk, JG, 192, 206 Hautmann, G, 30, 47 Havu, N, 192, 206

333 Hawroth, SG, 37, 51 Hay, DWP, 22, 30, 31, 33, 43, 48, 49 Hayashi, S, 31, 48 Hazinski, TA, 244, 263 Heading, RC, 96, 110 Hebbeln, H, 187, 205 Heberden, W, 116, 136 Hebert, CA, 24, 25, 45 Hecht, C, 306, 319 Hechtman, HB, 24, 44, 45 Hegele, R, 31, 48 Heimbucher, J, 224, 230, 235, 258, 267 Heine, R, 274, 282 Heinrich, C, 96, 110, 167, 177, 183, 204, 247, 263 Heldt, GP, 240, 244, 245, 246, 262, 275, 283 Helm, JF, 73, 79, 87, 291, 301 Henry, RL, 241, 262, 275, 283 Hentschel, E, 187, 205 Herbison, GP, 21, 43 Herbst, JJ, 60, 68, 237, 239, 255, 260, 261, 273, 274, 276, 281, 284 Hernandez, C, 28, 46 Herve, P, 20, 33, 41, 95, 109, 150, 151, 158, 174 Hervonen, A, 37, 51 Herz, R, 255, 266 Hetzel, D, 61, 68 Hetzel, DJ, 104, 112, 214, 234 Hetzel, DP, 292, 301 Heudebert, GR, 83, 88 Hevre, P, 248, 265 Hewitt, CJ, 21, 43 Hewson, EG, 56, 67 Hey, JA, 31, 48 Heym, C, 26, 38, 45 Higenbottom, T, 26, 45 Hill, LD, 225, 235, 236 Hillman, AL, 83, 88, 182, 204 Hilman, BC, 237, 255, 260 Himpens, J, 260, 267 Hind, CRK, 216, 235, 316, 322 Hinder, RA, 223, 229, 235 Hine, MK, 294, 301 Hintz, J, 308, 309, 320

334 Hirata, N, 28, 29, 46 Hirayama, Y, 23, 31, 42 Hirsch, B, 272, 281 Hirsch, W, 254, 266 Hirschowitz, BI, 81, 88, 189, 192, 206 Hislop, AA, 37, 51 Hiss, J, 77, 87 Hobson, CE, 26, 45 Hodgson, TA, 246, 263 Hoeffel, JC, 260, 267 Hoeft, SF, 222, 226, 235 Hoffer, DK, 243, 263 Hoffman, B, 37, 38, 51 Hoffman, CL, 240, 261 Hoffman, PJ, 20, 41, 92, 93, 94, 95, 96, 97, 99, 102, 103, 108 Hoffman, R, 308, 309, 320 Hoffpauir, J, 37, 52 Hoffstein, V, 90, 103, 106 Hofman, CL, 100, 102, 111 Hofmann, CL, 304, 319 Hogan, NJ, 240, 261 Hogan, SP, 23, 43 Hogan, WJ, 100, 102, 111, 156, 175, 244, 263, 270, 280, 291, 301, 304, 308, 309, 315, 319, 320, 322 Hokanson, JA, 306, 319 Hokfelt, T, 26, 30, 37, 39, 45, 51 Holbrook, WP, 239, 261, 291, 292, 301 Holdaway, MD, 21, 43 Holder, TM, 276, 284 Holgate, ST, 20, 21, 22, 31, 41, 42, 48 Holinger, LD, 90, 103, 107, 243, 262 Hollender, L, 93, 97, 98, 109, 142, 148, 157, 158, 173, 180, 203 Hollis, JB, 309, 320 Holloway, RH, 163, 176, 183, 204, 308, 320 Hollwarth, ME, 255, 266 Holmes, PW, 161, 162, 169, 176 Holt, S, 81, 88, 189, 192, 206 Holtzman, MA, 33, 49 Holzer, P, 20, 25, 26, 41 Hongo, M, 183, 204 Hood, CI, 24, 44, 216, 228, 235 Horback, JMLM, 224, 228, 230, 235

Author Index Horowitz, RI, 122, 137 Horton, PF, 61, 68 Hosie, KB, 214, 234 Hotz, P, 289, 301 Howarth, PH, 20, 21, 31, 41, 48 Howden, CW, 182, 204 Howden, GF, 285, 300 Hoyoux, C, 90, 108 Hrabovsky, EE, 272, 281 Hsu, SO, 275, 283 Hubbard, W, 33, 49 Huber, HL, 20, 41 Huber, RM, 167, 177, 183, 204, 247, 263 Hubert, D, 167, 177, 183, 204 Hughes, D, 310, 321 Hughes, DM, 95, 105, 110, 119, 136 Hughes, DMN, 247, 249, 263 Humbert, M, 24, 44 Hunter, J, 259, 267 Hureau, J, 163, 176 Hurwitz, A, 310, 312, 320 Huttemann, W, 187, 205 Huxley, EJ, 97, 110, 307, 309, 319 Hyams, JS, 255, 266, 272, 281 Hyman, PE, 270, 279, 280 Hyvarinen, H, 286, 290, 300

I Iascone, C, 105, 113, 125, 126, 137, 170, 171, 178, 197, 207, 217, 232, 235 Ichinose, M, 23, 31, 38, 42, 52, 53 Idrissi, MSS, 224, 228, 230, 235 Ikeda, H, 33, 49 Imaeda, H, 33, 50 Ing, AJ, 90, 92, 93, 94, 95, 96, 97, 98, 99, 107, 108, 109, 243, 263 Ingelfinger, FJ, 69, 87 Inocencion, G, 185, 205, 314, 321 Inoue, H, 38, 52, 53 International Asthma Project, 19, 40 Ireland, AP, 211, 212, 224, 228, 230, 234, 235, 258, 267

Author Index

335

Irvin, CG, 37, 38, 51 Irwin, RI, 90, 99, 103, 107 Irwin, RS, 20, 41, 56, 67, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 106, 107, 108, 110, 155, 170, 171, 172, 175, 178, 180, 203, 243, 262, 304, 310, 318, 320 Ismail-Beigi, F, 61, 68 Isolauri, E, 229, 236 Isolauri, J, 229, 236 Israel, D, 275, 284 Israel, E, 180, 204 Israel, RH, 90, 103, 107 Iwagoe, H, 28, 29, 46

J Jack, CIA, 156, 157, 158, 175, 215, 216, 234, 235, 316, 322 Jackson, C, 69, 87 Jackson, M, 28, 46 Jacob, P, 308, 320 Jacobs, F, 33, 48 Jacobson, KW, 165, 166, 177, 247, 263, 274, 282 Jacoby, DB, 22, 39, 42, 54 Jain, NK, 163, 176 Jammes, Y, 38, 52 Jancso, N, 26, 38, 45 Jancso-Gabor, A, 26, 38, 45 Janowitz, WR, 90, 93, 107, 155, 156, 175 Jansen, HM, 104, 112, 192, 194, 206, 257, 267 Jansen, JB, 192, 206 Jansen, JBMJ, 83, 88 Janson, C, 285, 300 Janssens, J, 98, 99, 101, 110, 111 Jarvinen, V, 286, 290, 295, 300, 301 Jarvis, D, 31, 48 Jeffery, PK, 24, 44 Jenkins, GN, 298, 302 Jenkins, WG, 288, 290, 292, 301 Jian, R, 20, 33, 41, 95, 109, 150, 151, 158, 174, 248, 265

Jiminez-Isabel, MA, 239, 261 Jindal, JR, 70, 86 Joelsson, B, 131, 138, 165, 167, 177 Johannesson, N, 131, 138, 165, 167, 177 Johns, DN, 309, 320 Johnson, D, 274, 283 Johnson, DA, 93, 109 Johnson, DG, 252, 258, 259, 266, 267, 276, 284 Johnson, L, 270, 280 Johnson, LF, 62, 68, 94, 96, 103, 109, 110, 112, 155, 156, 162, 175, 176, 183, 204, 217, 235, 291, 301 Johnson, WE, 196, 199, 207, 232, 236 Johnston, BT, 90, 107 Jolley, SG, 274, 276, 283, 284 Jones, B, 140, 141, 173, 242, 262, 304, 318 Jones, ME, 306, 319 Joos, GF, 23, 30, 42, 47 Joseph, GJ, 291, 301 Jouin, H, 93, 97, 98, 109, 125, 126, 137 Jovin, H, 142, 148, 157, 158, 173, 180, 203 Juodis, E, 275, 283 Just, R, 192, 206

K Kadakia, SC, 183, 204 Kadden, M, 24, 44, 165, 177, 183, 204, 247, 263, 274, 281 Kahn, A, 274, 275, 282 Kahrilas, PJ, 65, 68, 71, 72, 81, 83, 87, 88, 103, 104, 112, 161, 176, 183, 204, 237, 238, 240, 242, 243, 250, 260, 261, 285, 300, 308, 320 Kalia, M, 34, 50 Kaliner, MA, 33, 49, 161, 176 Kallay, MC, 90, 103, 107 Kallenback, JC, 162, 176 Kamada, SK, 180, 203 Kambie, V, 239, 261 Kamboj, L, 185, 205, 314, 321

336 Kamel, P, 104, 112 Kamel, PL, 71, 72, 81, 83, 87, 88, 240, 261 Kangas, M, 298, 301 Kanno, T, 39, 53 Karakousis, PC, 30, 35, 38, 47 Karl, S, 279, 284 Karlsson, JA, 92, 108, 140, 160, 173 Karvonen, A, 229, 236 Kashima, H, 310, 320 Katayama, H, 24, 45 Katsumata, U, 38, 53 Katz, AJ, 273, 281 Katz, PO, 62, 63, 65, 68, 83, 88, 99, 111, 216, 235 Katz, RM, 24, 44, 90, 92, 99, 108, 165, 177, 244, 247, 263, 274, 281, 282 Katzka, DA, 192, 206, 256, 267 Kauer, WKH, 196, 199, 207, 211, 212, 224, 230, 234, 235, 236, 258, 267 Kaufman, JA, 56, 67 Kaul, B, 98, 99, 111 Kavuru, MS, 180, 181, 203 Kawahara, H, 270, 280 Kawano, O, 28, 29, 46 Kay, AB, 20, 21, 23, 24, 42, 43, 44 Kaye, GM, 310, 321 Kaye, MD, 186, 188, 205 Kays, JS, 22, 28, 31, 39, 43 Kedan, R, 254, 266 Keen, MS, 306, 308, 310, 319 Keens, T, 275, 283 Keir, R, 33, 49 Keith, IM, 37, 51 Kempster, GB, 308, 309, 320 Kennedy, JH, 117, 136 Kern, M, 308, 309, 320 Kerr, GD, 125, 126, 137, 186, 188, 205 Kerr, P, 162, 176 Keyrilainen, O, 229, 236 Khan, A, 93, 109 Khandelwal, S, 24, 44, 56, 60, 63, 67, 68, 125, 126, 128, 129, 131, 134, 137, 138, 150, 160, 163, 168, 169, 170, 174, 175, 176, 180, 196, 197,

Author Index 199, 200, 203, 207, 211, 214, 217, 234, 235, 247, 263 Kianmanesh, R, 224, 228, 230, 235, 260, 267 Kikendall, JW, 183, 204 Kimmitt, P, 24, 44 Kimura, K, 38, 53 Kingsnorth, AN, 214, 234 Kinsbourne, M, 251, 265 Kirk, CL, 270, 279 Kirubakaran, C, 270, 280 Kita, H, 21, 43 Kitchin, LI, 182, 204 Kjellen, G, 143, 148, 157, 173, 184, 205 Kjellman, NIM, 129, 130, 138, 247, 263 Kjellman, WIM, 256, 258, 267 Klauser, A, 272, 281 Klauser, AG, 99, 111 Klein, M, 244, 263 Kleinsasser, O, 70, 71, 78, 86 Klemetti, E, 239, 261, 286, 289, 291, 300 Klinkenberg-Knol, EC, 81, 83, 88, 192, 206 Knoblich, R, 244, 263 Knuff, TE, 83, 88 Kobara, M, 308, 320 Kobzik, L, 24, 30, 37, 44, 45, 51 Koch, A, 276, 284 Koch, KL, 98, 101, 110 Kocoshis, SA, 241, 262, 275, 283 Koessler, KK, 20, 41 Kofman, J, 123, 124, 137 Kohrogi, H, 28, 29, 46 Kohut, RI, 70, 73, 78, 86 Kokonos, M, 95, 109, 152, 153, 154, 155, 158, 160, 175 Kolut, RI, 242, 262 Konig, A, 96, 110 Koren, G, 185, 205, 314, 321 Korpas, J, 92, 108 Koufman, JA, 62, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 98, 99,

Author Index

337

111, 156, 175, 239, 242, 243, 245, 261, 262, 316, 322 Kozarek, RA, 225, 236 Kraemer, SJM, 225, 236 Krause, JE, 32, 48 Kravitz, E, 251, 252, 256, 257, 265 Krekel, J, 37, 52 Kreutner, W, 23, 43 Kristleifsson, G, 239, 261, 291, 292, 301 Kron, IL, 26, 45 Kronborg, IJ, 152, 174, 192, 194, 196, 206 Kroon, L, 289, 301 Krugler, C, 308, 320 Kryger, MH, 162, 176 Kuck, EJ, 24, 44 Kuhns, L, 257, 267 Kuittnen, T, 298, 301 Kummer, W, 26, 28, 30, 31, 33, 34, 35, 37, 38, 39, 45, 47, 49, 52, 53 Kunkel, G, 23, 31, 42 Kuo, B, 66, 68, 152, 174 Kurkowski, R, 26, 38, 45 Kurose, I, 33, 50 Kurucar, C, 123, 124, 129, 137 Kurup, VP, 21, 43 Kusano, M, 309, 320

L L’Estrange, PL, 287, 300 Labarre, JF, 90, 107 Lacey, SR, 258, 267 Lacoste, JY, 20, 21, 41 Lacronique, J, 30, 47 Lagente, V, 33, 49 Lahdenuso, A, 90, 107 Laitinen, LA, 37, 51 Laitman, JT, 271, 280, 315, 321 Lama, A, 38, 52 Lambert, J, 256, 266 Lambiase, A, 33, 49

Lambrechts, L, 90, 108 Lamers, CB, 192, 206, 224, 228, 230, 235 Lami, CA, 189, 206, 257, 267 Lander, M, 272, 273, 280, 281 Lang, IM, 308, 309, 310, 320 Lange, RC, 163, 176 Langley, JN, 35, 50 Langman, J, 163, 176 Langou, RA, 122, 137 Langtry, HD, 81, 88 Lanza, F, 189, 192, 206 Lapicque, JC, 105, 113, 125, 126, 137 LaPointe, LL, 306, 319 Larrain, A, 20, 24, 41, 56, 60, 67, 125, 126, 137, 170, 171, 172, 178, 186, 188, 196, 197, 205, 260, 267, 279, 284 Larsen, GL, 38, 53, 119, 129, 130, 136, 138, 143, 144, 148, 157, 173, 248, 249, 265, 273, 281 Larson, JD, 314, 321 Larsson, O, 37, 51 Laughlin, GM, 245, 263 Laukka, MA, 90, 108 Laurence, BH, 214, 234 Law, SKY, 230, 236 Lawrence, LF, 90, 93, 107 Lazarchik, DA, 98, 111, 286, 288, 291, 292, 300, 301 Lazarus, S, 38, 53 Lazarus, SC, 180, 204 Leandro, G, 105, 113, 185, 205 Lebenthal, E, 270, 279 Lecocguic, Y, 247, 265 Ledbetter, MS, 242, 262 Leduc, T, 168, 177, 183, 205 Lee, A, 187, 205 Lee, JC, 273, 274, 281 Lee, P, 33, 49, 270, 279 Lefevre, PM, 26, 46 Leff, AR, 314, 321 Leite, L, 256, 267 Lemanske, RF, 180, 204 Lemen, RJ, 244, 263

338 Lemper, JC, 260, 267 Leport, J, 224, 228, 230, 235, 260, 267 Lerner, E, 244, 263 Lester, LA, 275, 283 Levi-Schafer, F, 21, 43 Levin, B, 308, 310, 319 Levison, H, 95, 105, 110, 119, 136, 247, 249, 263, 275, 283 Levy, BM, 294, 301 Levy, GP, 37, 51 Lew, C, 275, 283 Lewis, J, 279, 284 Lewis, T, 20, 25, 26, 31, 41 Li, BUK, 259, 267 Li, Q, 100, 102, 111, 240, 261, 304, 319 Lichtenstein, LM, 20, 21, 22, 23, 42 Liew, VP, 286, 300 Lilly, CM, 31, 48 Lindahl, H, 276, 284 Lindgren, BR, 170, 171, 172, 178, 186, 187, 188, 205 Lindsey, JR, 26, 46 Liron, R, 214, 234 Little, AG, 161, 175 Little, FB, 70, 73, 78, 86, 242, 262 Little, JP, 70, 80, 86 Litwin, D, 180, 181, 203 Liu, J, 308, 309, 320 Liu, YC, 155, 175 Llyod, DA, 162, 176 Lo Cascio, V, 94, 95, 109 Loader, JE, 38, 53 Locke, GR, 56, 67, 180, 197, 203, 304, 319 Lockhart, A, 167, 177, 183, 204 Lodi, U, 147, 148, 150, 162, 169, 174 Lof, GL, 308, 309, 320 Loftor,DW, 257, 267 Logemann, JA, 308, 320 Lomansey, TL, 105, 113 Lombard-Platet, R, 20, 24, 41, 170, 171, 172, 173, 178, 196, 198, 207 Lomena, F, 272, 274, 280 Londong, W, 272, 281

Author Index Lopez, AF, 19, 23, 40 Lorenzetti, BB, 33, 49 Lotti, T, 30, 47 Loughlin, CJ, 70, 76, 77, 81, 86, 87, 316, 322 Loughlin, GM, 90, 107, 243, 274, 263, 282 Louhimo, I, 276, 284 Low, DE, 225, 235 Lowenstein, CJ, 37, 39, 51 Lowry, R, 26, 45 Luce, D, 78, 88 Luckers, A, 192, 206 Luckmann, K, 252, 266 Ludviksdottir, D, 285, 300 Lundberg, JM, 26, 28, 30, 31, 34, 37, 38, 39, 45, 46, 50, 51, 52 Luostarinen, M, 229, 236, 259, 267 Lussi, A, 289, 301 Lutz, J, 270, 280 Lyrenas, E, 274, 282

M MacGlashan, DW, 24, 44 Machida, HM, 257, 267 MacIagan, J, 39, 53 Mackinnon, M, 104, 112 Mackinnon, WD, 214, 234 Macklem, PT, 37, 38, 51, 165, 169, 177, 247, 263 Macklin, CC, 25, 45 Maclagan, J, 28, 31, 39, 47 Madgy, DM, 240, 262 Magee, LA, 185, 205, 314, 321 Maggi, CA, 25, 26, 45 Maggi, JC, 93, 108, 155, 175 Magrini, L, 33, 49 Maher, J, 274, 282 Maimonides, M, 116, 136 Maisels, M, 275, 279, 283, 284 Malagelada, JR, 99, 111 Maldonado, J, 95, 109 Malfroot, A, 105, 113, 275, 283

Author Index Malmagyi, DFJ, 152, 174 Malmgren, LT, 306, 310, 319, 320 Mandel, ID, 292, 301 Mangano, M, 315, 322 Mannerberg, F, 292, 301 Manni, L, 33, 49 Mansfield, LE, 20, 40, 41, 92, 93, 95, 108, 109, 140, 142, 148, 157, 158, 165, 166, 167, 173, 177, 248, 265, 273, 274, 281, 282 Mansfield, TE, 247, 263 Mansson, I, 155, 175, 316, 322 Maples, RV, 147, 148, 158, 174 Marano, MA, 246, 263 Marcinkiewicz, M, 298, 302 Marco, V, 95, 109, 180, 197, 203 Margulies, SI, 69, 70, 71, 86, 117, 136 Marinkovich, VA, 129, 130, 138 Marino, W, 274, 282 Markewitz, BA, 22, 33, 43 Marks, R, 83, 88 Marmon, L, 275, 283 Marques, L, 257, 267 Marsac, J, 167, 177, 183, 204 Marshall, RB, 242, 262 Martin, JH, 306, 308, 310, 319 Martin, ME, 129, 130, 138 Martin, RJ, 144, 158, 174, 180, 203, 248, 265 Martin, RR, 37, 38, 51 Martin, TR, 21, 43 Martinez de Haro, LF, 214, 234 Martling, CR, 26, 28, 30, 31, 37, 39, 45, 46, 51 Masclee, AAM, 224, 228, 230, 235 Massarella, GR, 20, 41 Mathay, MA, 24, 25, 45 Mathews, JK, 38, 53 Mathis, R, 93, 108, 155, 175 Matlak, ME, 276, 284 Maton, PN, 189, 206 Matran, R, 35, 37, 51 Matsuda, T, 33, 49, 90, 107 Matsumoto, S, 39, 53 Matsuse, T, 24, 33, 45, 49

339 Matsushima, K, 33, 49 Matthaei, KI, 23, 43 Matthews, BL, 70, 80, 86 Mattoli, S, 254, 266 Mattox, HE, 96, 99, 110 Matute-Cardenas, JA, 239, 261 Mauser, PJ, 23, 43 Maxwell, SL, 307, 309, 319 Maydonovitch, C, 183, 204 Mayer, B, 37, 38, 51, 53 Mays, EE, 125, 128, 138, 161, 163, 176, 180, 197, 203 McCallum, RW, 99, 111, 163, 176, 183, 204, 292, 298, 301, 302 McCarson, KE, 32, 48 McCarthy, JH, 214, 234 McCloy, RF, 99, 111 McCombs, A, 276, 284 McConnell, F, 310, 320 McCourtie, DR, 162, 176 McDonald, DM, 22, 26, 28, 31, 39, 42, 45, 46, 47 McDonnell, JT, 165, 166, 177, 247, 263, 274, 282 McGeady, SJ, 250, 251, 252, 256, 257, 265 McGregor, GP, 33, 49 McKay, K, 31, 48 McLeod, RL, 31, 48 McMahan, J, 104, 112 McNally, EF, 103, 112 McNally, PR, 170, 172, 177, 192, 193, 194, 206 McTavish, D, 189, 192, 206 Mehlhop, PD, 21, 43 Meier, JH, 170, 172, 177, 192, 193, 194, 206 Mela, GS, 185, 205 Meli, A, 25, 26, 45 Mellis, CM, 241, 262, 275, 283 Mello, CJ, 90, 92, 96, 97, 98, 99, 101, 103, 106, 110, 243, 262 Mellow, MH, 103, 112 Melton, LJ, 56, 67, 180, 197, 203 Meltzer, SJ, 69, 87

340 Menanteau, B, 253, 266 Menchausky, B, 180, 203 Meng, Q, 24, 44 Menon, AP, 274, 282 Menz, G, 24, 44 Meraud, P, 90, 108 Mertz, H, 270, 280 Mesulam, MM, 34, 50 Methlin, G, 14, 93, 97, 98, 109, 148, 157, 158, 173, 180, 203 Metwally, N, 309, 320 Meunier, L, 38, 53 Meurman, JH, 286, 289, 290, 291, 295, 298, 300, 301 Meuwissen, SG, 81, 88, 192, 206 Meyer, C, 93, 97, 98, 109, 125, 126, 137, 142, 148, 157, 158, 173, 180, 203 Meyer, E, 270, 280 Meyers, WF, 252, 266 Michael, JR, 22, 33, 43 Michel, FB, 20, 21, 42 Michel, ME, 183, 204 Michoud, MC, 168, 177, 183, 205 Mickey, MR, 165, 177, 247, 263, 274, 281 Mickflikier, AB, 162, 176 Miki, K, 270, 279 Milbrath, MM, 70, 86, 100, 102, 111, 240, 261, 304, 319 Miles, JF, 179, 197, 203 Millar, NSC, 162, 176 Millar, T, 162, 176 Miller, FA, 69, 87 Miller, SA, 20, 41, 143, 145, 148, 157, 158, 173 Miller, SJ, 123, 124, 129, 137 Miller, T, 24, 44, 56, 67, 122, 123, 124, 125, 126, 128, 129, 131, 134, 137, 138, 160, 163, 168, 169, 170, 175, 176, 180, 196, 197, 199, 200, 203, 207, 211, 214, 234, 247, 263 Mills, SE, 26, 45 Milner, AD, 274, 282 Minella, R, 270, 275, 280, 283

Author Index Miner, PB, 314, 321 Minton, J, 306, 319 Minton, SD, 60, 68, 273, 274, 281 Miralbes, M, 180, 197, 203 Mitchell, B, 214, 234 Mitchell, I, 275, 283 Mittal, R, 161, 162, 163, 164, 169, 175, 176, 247, 263 Miura, M, 23, 31, 38, 42, 52, 53 Miura, S, 33, 50 Mizuguchi, M, 33, 49, 90, 107 Mobassaleh, M, 256, 266 Modell, JH, 24, 44 Moffatt, JD, 34, 35, 50 Mogi, G, 318, 322 Mohr, JP, 308, 310, 319 Molimard, M, 30, 31, 47 Molina, J, 214, 234 Moore, DJ, 253, 266 Moote, DW, 162, 176 Morabito, A, 285, 300 Morales, G, 214, 234 Morgan, TM, 96, 110 Morley, J, 33, 34, 49 Morris, BA, 244, 263 Morris, JL, 35, 50 Morrison, MD, 70, 78, 86 Mortelliti, AJ, 306, 319 Mosher, HP, 69, 87 Mosmann, TR, 21, 43 Mosnier, H, 224, 228, 230, 235, 260, 267 Moulin, D, 129, 130, 138, 240, 261 Muller-Lissner, SA, 99, 111, 167, 177, 183, 204, 247, 263, 272, 281 Mullett, MD, 272, 281 Muls, V, 260, 267 Munciano, D, 247, 265 Murat, BW, 96, 99, 110 Murphy, DW, 103, 112 Murphy, SA, 275, 283 Murtomaa, H, 286, 290, 300 Myers, AC, 22, 28, 29, 30, 31, 33, 39, 43, 46, 47, 48, 54 Myracle, J, 241, 262 Myrvold, HE, 98, 99, 111

Author Index

341 N

N’Duwlmana, M, 274, 275, 282 Nadel, JA, 26, 28, 31, 33, 38, 39, 45, 46, 47, 48, 49, 53, 97, 110, 248, 265 Nagase, T, 24, 45 Nagata, H, 33, 50 Nagayama, T, 39, 53 Nagel, RA, 125, 126, 137, 186, 188, 205 Naik, DR, 253, 266 Nakajima, N, 23, 31, 42 Naline, E, 30, 31, 47 Namiot, Z, 292, 301 Narcy, P, 70, 75, 80, 86, 239, 240, 241, 253, 261, 315, 321 Nardi, R, 99, 111 Narielvala, RM, 104, 112, 214, 234 Nash, M, 93, 109 National Heart, Lung and Blood Institute, 19, 40 Naveh, Y, 273, 281 Neary, P, 223, 229, 235 Nebel, OT, 56, 67 Nelis, F, 192, 206 Nelson, HS, 165, 166, 177, 247, 252, 255, 263, 266, 274, 282, 317, 322 Nelson, JL, 309, 320 Nemchausky, B, 20, 24, 40, 44, 125, 126, 129, 131, 134, 137, 138, 160, 169, 170, 175, 196, 198, 207, 211, 214, 234, 247, 263 Nemchausky, T, 196, 197, 199, 200, 207 Netzer, P, 96, 110 Neuhauser, EBD, 69, 80, 87 Neurna, JH, 239, 261 Newhouse, MT, 90, 95, 99, 103, 104, 105, 106, 107, 110 Ngu, MC, 90, 92, 93, 94, 95, 96, 97, 98, 99, 107, 109, 243, 263 Nieber, K, 23, 31, 42 Nielson, DW, 240, 244, 245, 246, 262, 275, 283

Nihoul-Fekete, C, 260, 267 Nishi, K, 33, 49, 90, 107 Nixon, TE, 95, 105, 110, 274, 282 Nogami, H, 38, 52 Nohr, D, 37, 52 Nomura, M, 33, 49 Noordzij, P, 70, 79, 86 Nouvet, G, 20, 40 Nouvet, TG, 196, 198, 207 Novak, LB, 38, 53 Novembre, E, 189, 206, 257, 267 Novey, HS, 119, 137 Nowak, L, 71, 87 Nussbaum, E, 93, 108, 155, 175 Nutinen, P, 239, 261 Nuutinen, P, 286, 289, 291, 300

O O’Connell, EJ, 317, 322 O’Connell, F, 103, 112 O’Connell, S, 20, 24, 40, 44, 56, 60, 63, 67, 68, 123, 124, 125, 126, 128, 129, 131, 134, 137, 138, 150, 160, 163, 168, 169, 170, 174, 175, 176, 180, 196, 197, 198, 199, 200, 203, 207, 211, 214, 217, 234, 235, 247, 263 O’Donnell, M, 37, 38, 51 O’Neal, M, 275, 283 O’Reilly, S, 31, 48 Oakley, GD, 56, 60, 67 Obach, S, 33, 49 Oehme, P, 23, 31, 42 Oestreich, A, 271, 280 Oettgen, HC, 21, 43 Oggero, V, 275, 283 Ohga, E, 24, 45 Ohka, T, 33, 49 Okubo, T, 33, 49 Oldham, KT, 259, 267, 279, 284 Olinksy, A, 274, 282 Oliver, PS, 104, 112, 192, 193, 194, 206

342

Author Index

Oliviera, H, 37, 51 Olivieri, M, 94, 95, 109 Ollerenshaw, SL, 31, 48 O’Loughlin, EV, 275, 283 Olson, NR, 70, 71, 73, 78, 86 Omari, T, 270, 279 Once, J, 180, 197, 203 Ong, TH, 272, 273, 280, 281 Ooka, T, 90, 107 Opdenakker, G, 24, 44 Orenstein, DM, 238, 241, 257, 260, 262, 267, 272, 275, 280, 283 Orenstein, S, 98, 99, 111, 238, 239, 240, 241, 244, 245, 246, 251, 252, 253, 255, 256, 257, 259, 260, 261, 262, 263, 266, 267, 270, 272, 273, 275, 278, 280, 281, 283, 284 Oritz, A, 214, 234 Orlando, RC, 96, 98, 99, 103, 105, 110, 182, 204 Orr, WC, 99, 103, 111, 112 Orringer, MB, 224, 225, 228, 230, 235, 236 Osborn, RR, 38, 53 Osler, WB, 116, 136, 139, 140, 173, 246, 263 Ossakow, DJ, 69, 70, 71, 72, 79, 86 Ote, JB, 184, 205 Otis, RD, 152, 174 Otsuka, M, 26, 30, 45 Ott, DJ, 59, 67, 81, 88, 242, 252, 262, 266 Otte, JB, 129, 130, 138, 240, 261 Overholt, RH, 119, 136, 152, 174

P Pace, F, 311, 313, 321 Pack, AI, 95, 105, 109, 110, 144, 152, 153, 154, 155, 158, 160, 174, 175 Page, C, 19, 40 Palmer, ED, 65, 68 Palombini, B, 37, 38, 51 Palot, JP, 163, 176

Panagopoulos, V, 308, 320 Panconesi, E, 30, 47 Pandey, R, 144, 158, 174 Panetti, M, 71, 87 Pantalena, M, 105, 113, 185, 205 Paoletti, V, 256, 267 Pariente, R, 247, 265 Parker, AF, 276, 284 Parkes, MW, 38, 53 Parrilla, P, 214, 234 Parsons, DS, 318, 322 Partanen, M, 37, 51 Pasquis, P, 20, 40, 196, 198, 207 Passot, E, 90, 107 Pastma, GN, 71, 87 Patacchini, R, 26, 45 Patatanian, E, 314, 321 Patel, B, 78, 88, 183, 204 Paterson, WG, 96, 99, 110 Pathial, K, 156, 175 Patterson, D, 33, 49 Patterson, JE, 214, 234 Paulson, DL, 117, 136 Pauwels, RA, 23, 30, 42, 47 Pearlman, DS, 239, 261 Peat, JK, 21, 43 Pecau, Y, 275, 283 Pecova, R, 91, 108 Pedersen, KE, 22, 42 Peghini, P, 65, 68 Pellegrini, CA, 162, 176, 217, 235 Pellett, JR, 259, 267 Pellicer, C, 95, 109 Pelto-Huikko, M, 37, 51 Pelttari, A, 289, 301 Pen, J, 240, 261 Penagini, R, 163, 176 Perdikis, G, 223, 229, 235 Perin, P, 250, 265 Perks, WH, 125, 126, 137, 186, 188, 205 Perlman, LV, 244, 263 Permutt, S, 38, 53 Perpina, M, 95, 109, 180, 197, 203 Perrault, S, 168, 177, 183, 205

Author Index Perrin-Fayolle, M, 20, 24, 41, 119, 123, 124, 137, 170, 171, 172, 173, 178, 196, 198, 207, 246, 263 Perry, M, 170, 172, 177, 192, 193, 194, 206 Persson, CGA, 131, 138, 165, 167, 177 Pesendorfer, P, 255, 266 Peters, JH, 196, 197, 199, 207, 211, 212, 214, 222, 224, 226, 228, 230, 234, 235, 258, 267 Peters, M, 31, 48 Petersen, H, 98, 99, 111 Pfister, R, 24, 44 Phelan, P, 274, 282 Philbrick, JT, 122, 137 Philip, G, 30, 47 Philippin, B, 33, 49 Phillips, AM, 89, 107 Phillips, RW, 89, 107 Piascik, R, 292, 301 Piedimonte, G, 28, 46 Pien, L, 180, 181, 203 Piepsz, A, 105, 113 Pierce, AK, 97, 110, 307, 309, 319 Pieretti, R, 276, 284 Pilotto, A, 105, 113, 185, 205 Pindborg, JJ, 287, 300 Piper, DW, 81, 88 Pitchumoni, C, 274, 282 Pitman, AM, 23, 43 Plaschkes, J, 276, 284 Plaxico, D, 274, 282 Plebani, M, 105, 113, 185, 205 Podvran, B, 308, 309, 310, 320 Poe, RH, 90, 103, 107 Pohl, J, 255, 266 Polak, JM, 31, 37, 48, 51, 52 Pollmann, H, 255, 266 Polonovski, JM, 240, 261 Ponce, J, 95, 109 Ponce-Castro, H, 104, 112 Pondez, R, 248, 265 Pontoppidan, H, 307, 319 Poole, S, 33, 49 Pope, CE, 20, 24, 41, 61, 68, 99, 111,

343 125, 126, 137, 163, 170, 171, 172, 176, 178, 182, 186, 188, 196, 197, 204, 205, 248, 250, 260, 265, 267, 279, 284, 285, 300, 312, 321 Posavac, EJ, 122, 137 Postma, GN, 84, 88 Pratter, MR, 56, 67, 89, 90, 103, 106, 107 Preiss, U, 254, 266 Prescott, CA, 239, 261 Pride, NB, 103, 112 Prince, R, 247, 263, 274, 282 Prinsen, J, 275, 284 Prior, JS, 104, 112, 192, 193, 194, 206 Proud, D, 33, 49, 315, 321 Proujansky, R, 241, 262, 275, 283 Proulx, F, 168, 177, 183, 205 Puetz, TR, 106, 113 Pulijoki, H, 90, 107 Punja, M, 170, 172, 177, 192, 193, 194, 206 Putnam, PE, 98, 99, 111, 240, 252, 261, 262, 273, 281

Q Quan, SF, 20, 22, 23, 42

R Rachelefsky, GS, 24, 44, 90, 92, 99, 108, 165, 177, 183, 204, 244, 247, 263, 274, 281, 282 Rademaker, AW, 65, 68 Radsel, Z, 239, 261 Rajan, A, 260, 267 Ramirez, B, 98, 111, 286, 291, 292, 300, 301 Ramphal, R, 216, 228, 235 Ramsay, AJ, 23, 43 Ransohoff, DF, 122, 137 Rathsack, R, 23, 31, 42

344 Ravich, WJ, 140, 141, 173, 242, 262, 304, 318 Ray, DW, 28, 46 Rayburn, WF, 314, 321 Reboud, E, 105, 113, 125, 126, 137 Rebuffat, E, 274, 275, 282 Reed, WD, 61, 68, 104, 112, 214, 234, 286, 300 Regoli, D, 30, 31, 47 Rehm, D, 270, 280 Reichelderfer, M, 103, 112 Reid, RH, 155, 175 Reid, S, 123, 124, 129, 137 Reidenberg, J, 271, 280 Reinach, SG, 162, 176 Reisner, C, 317, 322 Ren, J, 304, 308, 309, 319, 320 Resti, M, 189, 206, 257, 267 Reulbach, TR, 84, 88 Revillon, Y, 247, 248, 265 Reyes, C, 276, 284 Riccio, MM, 29, 33, 47, 49 Richards, J, 244, 263 Richardson, CA, 38, 52 Richardson, J, 37, 51 Richter, JE, 19, 20, 24, 40, 41, 56, 59, 60, 62, 63, 66, 67, 68, 80, 88, 96, 98, 99, 100, 101, 104, 110, 111, 112, 145, 146, 147, 148, 156, 157, 158, 170, 172, 174, 175, 178, 179, 185, 192, 194, 197, 203, 205, 206, 207, 210, 234, 239, 250, 251, 255, 256, 257, 261, 265, 266, 286, 291, 292, 300, 301, 304, 309, 313, 314, 316, 319, 320, 321, 322 Ricker, DH, 240, 252, 262, 273, 281 Ricks, P, 252, 266 Riedel, DR, 73, 79, 87 Riedenberg, JS, 315, 321 Riera, C, 272, 274, 280 Rintala, R, 276, 284 Rio-Navarro, BE, 104, 112 Ritter, MP, 196, 199, 207, 211, 228, 234 Rivein, J, 247, 249, 263 Rivlin, J, 95, 105, 110, 119, 136

Author Index Robb, ND, 285, 300 Robbins, J, 308, 309, 320 Roberts, CC, 252, 266, 276, 284 Roberts, MW, 285, 300 Robinson, DS, 20, 21, 24, 42, 43, 44 Robinson, MG, 99, 103, 111, 112, 182, 189, 192, 204, 206, 314, 321 Robinson, P, 152, 174, 192, 194, 196, 206 Roca, I, 257, 267 Roche, WR, 20, 21, 41 Rochester, DF, 163, 176 Rodd, A, 37, 38, 51 Rodrigues-Roisin, R, 272, 274, 280 Rodriguez-Villarrel, H, 125, 126, 128, 138 Rodriquez de Quesada, B, 251, 265 Roessle, R, 270, 280 Roger, G, 70, 77, 80, 86, 87 Rogers, DF, 28, 31, 35, 37, 47 Rohr, S, 276, 284 Rohwedder, JJ, 168, 177, 183, 204, 274, 282 Rolla, G, 315, 322 Ron, J, 100, 102, 111 Roos, CM, 104, 112, 192, 194, 206, 257, 267 Ros, E, 272, 274, 280 Rosemeyer, D, 255, 266 Rosen, SN, 99, 111 Rosenwasser, L, 21, 43 Rosetti, F, 185, 205, 314, 321 Rosman, AS, 79, 88 Ross, A, 279, 284 Ross, JA, 70, 79, 86 Rothberg, RM, 275, 283 Rothwell, JC, 310, 321 Roulet, F, 270, 280 Rourk, RM, 292, 301 Roussos, C, 165, 169, 177 Roussos, E, 247, 263 Rovero, P, 26, 45 Rowshan, N, 274, 282 Rubin, S, 275, 283 Ruggins, NR, 274, 282 Ruhl, CE, 310, 312, 320

Author Index

345

Russell, G, 156, 157, 158, 175, 316, 322 Ruth, M, 155, 175, 316, 322 Ruzkowski, CJ, 168, 177, 183, 204, 274, 282 Ryabova, VS, 307, 309, 319 Ryan, P, 273, 281 Rytomaa, I, 286, 289, 290, 295, 300, 301

S Sacco, RL, 308, 310, 319 Sackner, MA, 98, 107 Sacre, L, 188, 205 Sacre-Smits, L, 270, 280 Sadek, SA, 183, 204 Sagar, PM, 214, 234 Said, SI, 37, 38, 51, 52 Saito, H, 33, 49 Sakamoto, T, 28, 46 Salari, H, 33, 49 Salem, H, 248, 265 Salome, CM, 21, 43 Salter, HH, 25, 31, 45 Samloff, IM, 310, 312, 320 Sampson, AP, 21, 22, 42 Sampson, M, 247, 263 Sand, C, 274, 282 Sandberg, N, 155, 175, 316, 322 Sanders, AD, 77, 87, 90, 103, 107, 243, 262 Sandler, A, 274, 282 Sandro Mela, G, 105, 113 Sangaletti, O, 311, 313, 321 Sanico, AM, 30, 47, 315, 321 Sann, H, 37, 52 Sanowski, RA, 168, 177, 183, 204, 274, 282 Sant’Ambrogio, G, 92, 108, 140, 160, 173 Santamaria, F, 275, 283 Sarahan, TM, 244, 263 Saria, A, 26, 28, 30, 31, 33, 34, 39, 45, 46, 49, 50

Sarna, A, 308, 309, 320 Sarosiek, J, 292, 298, 301, 302 Sasagawa, M, 90, 108 Sasaki, CT, 315, 321 Sataloff, RT, 69, 72, 81, 82, 83, 86 Satch, M, 90, 108 Sattilaro, AJ, 152, 174 Saubier, E, 90, 108 Savarino, V, 105, 113, 185, 205 Saye, Z, 105, 112, 189, 206 Sbai-Idrassi, MS, 260, 267 Scappaticci, E, 315, 322 Schaal, SE, 310, 312, 320 Schaffner, M, 289, 301 Schaible, HG, 32, 48 Schalling, M, 37, 51 Schan, CA, 20, 41, 104, 112, 145, 146, 147, 148, 157, 158, 170, 172, 174, 178, 250, 256, 257, 265 Schefft, GL, 274, 282 Schei, AJ, 90, 108 Schellenberg, RR, 33, 49 Schemann, M, 37, 52 Scheurich, CJ, 298, 302 Schidlow, DV, 246, 264, 275, 283 Schindlbeck, NE, 96, 99, 110, 111, 167, 177, 183, 204, 247, 263, 272, 281 Schleimer, RP, 21, 24, 43 Schmidt, A, 20, 41, 95, 109, 143, 158, 173 Schmidt, C, 77, 87, 274, 282 Schmidt, EV, 307, 309, 319 Schmidt, RF, 32, 48 Schmitt, M, 260, 267 Schnatz, PF, 63, 68, 90, 94, 99, 107, 170, 171, 172, 178, 216, 235 Schnell, TG, 20, 24, 40, 44, 56, 67, 125, 126, 128, 129, 131, 134, 137, 138, 160, 163, 168, 169, 170, 175, 176, 180, 196, 197, 198, 199, 200, 203, 207, 211, 214, 234, 247, 263 Schoeb, TR, 26, 46 Schroeder, JT, 24, 44 Schroeder, PL, 98, 111, 286, 291, 292, 300, 301, 316, 322 Schuck, TJ, 73, 87

346 Schultz, E, 187, 205 Schultz, HD, 26, 34, 45 Schwartz, DJ, 24, 44 Schwartz, J, 95, 109, 152, 153, 154, 155, 158, 160, 175 Schwartz, LB, 21, 22, 23, 42, 43 Schwartz, S, 182, 204 Schwiebert, LM, 21, 24, 43 Scott, RB, 257, 267, 275, 283 Searl, JP, 81, 88 Sears, MR, 19, 21, 40, 43 Sedgwick, JB, 21, 43 Seheinmann, P, 247, 248, 265 Seibert, J, 244, 263 Seidel, UJ, 24, 44, 125, 126, 128, 129, 137, 163, 168, 170, 176 Seidel, WJ, 180, 203 Seilheimer, DK, 275, 283 Sekizuka, E, 33, 50 Sellner, JC, 142, 148, 157, 158, 173, 273, 281 Sembenini, C, 94, 95, 109 Sepulveda, R, 20, 24, 41, 125, 126, 137, 170, 171, 172, 178, 186, 188, 196, 197, 205, 260, 267, 279, 284 Serizawa, H, 33, 50 Serlovsky, R, 24, 44, 125, 126, 129, 131, 134, 137, 138, 160, 169, 170, 175, 180, 203, 211, 214, 234 Serra-Battles, J, 272, 274, 280 Shafer, SG, 294, 301 Shah, B, 272, 281 Shaker, R, 69, 70, 72, 86, 93, 100, 102, 108, 111, 156, 175, 240, 261, 304, 308, 309, 310, 312, 314, 319, 320, 321 Shalaby, T, 270, 280 Shandling, B, 276, 284 Shannon, WA, 37, 51 Shapiro, GG, 129, 130, 138, 247, 263 Shatz, A, 77, 87 Shaw, DW, 308, 320 Shaw, GY, 81, 88 Sheahan, GG, 105, 113 Shearman, DJC, 104, 112, 214, 234

Author Index Shelhamer, JH, 161, 176 Sheller, JR, 33, 49 Shepherd, P, 273, 281 Shepherd, RW, 272, 280 Shepro, D, 24, 44, 45 Sherloosky, R, 247, 263 Shimizu, T, 39, 53 Shimizu, Y, 22, 23, 42 Shimosegawa, T, 37, 52 Shinoda, M, 318, 322 Shiozaki, H, 33, 50 Shirasaki, H, 31, 48 Shirato, K, 23, 31, 42 Shoenut, JP, 162, 176 Shore, SA, 31, 48 Shou-Hua, L, 285, 300 Siegel, SC, 24, 44, 90, 92, 99, 108, 165, 177, 244, 247, 263, 274, 281, 282 Sienra-Monge, JJ, 104, 112 Sigmund, CJ, 103, 112 Silver, PB, 33, 49 Silverberg, M, 272, 281 Silverman, M, 33, 50 Silverman, W, 247, 248, 249, 263 Simonneau, G, 20, 33, 41, 95, 109, 150, 151, 158, 174, 248, 265 Simonsson, B, 33, 48 Simony-Lafontaine, J, 20, 21, 42 Simpson, WG, 20, 41, 182, 204, 285, 300 Simula, ME, 308, 320 Sinclair, J, 103, 112, 183, 184, 204, 205 Sinclair, JW, 56, 67, 96, 110 Sindel, B, 275, 279, 283, 284 Singh, V, 163, 176 Siu, Z, 308, 309, 320 Skinner, DB, 105, 113, 125, 126, 137, 161, 162, 170, 171, 175, 176, 178, 197, 207, 217, 224, 228, 230, 232, 235, 291, 301 Skloot, G, 38, 53 Sloan, S, 65, 68, 161, 176 Smart, SJ, 25, 38, 39, 45 Smirnov, VE, 307, 309, 319 Smith, BGN, 285, 300

Author Index Smith, DL, 20, 21, 23, 42 Smith, H, 275, 284 Smith, LF, 56, 60, 67 Smith, LJ, 161, 176 Smith, N, 273, 281 Smith, NJ, 95, 109, 140, 142, 148, 157, 173 Smith, R, 274, 282 Smith, S, 279, 284 Smyrnios, NA, 89, 90, 92, 97, 98, 99, 103, 107, 304, 310, 318, 320 Snel, P, 192, 206 Snider, RM, 28, 46 Soergel, KH, 308, 320 Sognnaes, RF, 289, 301 Solcia, E, 104, 112 Soll, AH, 73, 87 Solway, J, 28, 46 Sondheimer, JM, 244, 263, 270, 279 Sonnenberg, A, 316, 322 Sontag, SJ, 20, 24, 40, 44, 56, 60, 63, 67, 68, 81, 88, 123, 124, 125, 126, 128, 129, 131, 134, 137, 138, 150, 160, 163, 168, 169, 170, 174, 175, 176, 180, 189, 192, 196, 197, 198, 199, 200, 203, 206, 207, 211, 214, 217, 234, 235, 247, 250, 263, 265 Sorvari, R, 289, 301 Spannhake, EW, 30, 48 Spaulding, HS, 95, 109, 140, 142, 148, 157, 158, 170, 172, 173, 177, 192, 193, 194, 206, 273, 281 Spechler, SJ, 62, 68, 105, 113, 229, 236 Spedding, C, 298, 302, 312, 321 Spier, S, 95, 105, 110, 119, 136, 247, 249, 263 Spitzer, AR, 95, 109, 152, 153, 154, 155, 158, 160, 175, 274, 282 Sprigg, A, 275, 283 Springall, DR, 31, 37, 48, 51, 52 Spurling, TJ, 56, 57, 60, 64, 67 St Vil, D, 129, 130, 138 Staiano, A, 270, 280 Stamler, JS, 37, 39, 51 Stanciu, C, 103, 112, 184, 205

347 Stealman, CR, 253, 266 Steens, RD, 162, 176 Stein, MR, 20, 41, 92, 93, 108, 131, 138, 142, 148, 155, 157, 158, 165, 166, 167, 173, 175, 177, 247, 248, 254, 263, 265, 266, 273, 274, 281, 282 Stellato, C, 21, 24, 43 Stephens, CA, 276, 284 Sterling, C, 274, 283 Stocker, N, 170, 172, 177, 192, 193, 194, 206 Stoddard, CJ, 214, 234 Stolar, CJ, 276, 284 Storz, C, 24, 44 Stow, RB, 26, 46 Stringer, D, 275, 283 Strobel, CF, 244, 253, 263, 266 Strobel, CT, 90, 92, 99, 108 Stulbarg, M, 90, 107 Sudduth, RH, 170, 172, 177, 192, 193, 194, 206 Sudo, E, 24, 45 Suematsu, M, 33, 50 Sugarbaker, D, 37, 39, 51 Sui, Z, 309, 310, 320 Suko, T, 318, 322 Sullivan, CE, 31, 48 Sunshine, S, 308, 310, 319 Surpas, P, 105, 113, 125, 126, 137 Suter, P, 289, 301 Sutphen, JL, 271, 280 Suzuki, E, 90, 93, 108 Svedberg, LE, 192, 206 Szefler, SJ, 180, 203 Szentivanyi, A, 25, 45 Szolcsanyi, J, 26, 38, 45

T Taborda-Barata, L, 24, 44 Tadjkarimi, S, 37, 51 Takahashi, T, 38, 53 Takeyama, M, 318, 322

348 Takishima, T, 38, 52, 53 Talbot, A, 318, 322 Talerico, SD, 26, 46 Talley, NJ, 56, 67, 180, 197, 203, 304, 319 Tallis, Rc, 310, 321 Taminiau, JA, 253, 266 Tamplin, B, 248, 265 Tan, WC, 144, 158, 174, 248, 265 Tardif, C, 196, 198, 207 Tardiff, C, 20, 40 Tashiro, H, 33, 50 Tatar, M, 91, 108 Tatemoto, K, 37, 51 Taussig, LM, 240, 262 Taylor, LA, 258, 267 Teague, WG, 26, 45 Teare, JP, 298, 302, 312, 321 Teichtahl, H, 152, 174, 192, 194, 196, 206 Temple, JG, 24, 44 ten Velde, GPM, 144, 158, 174, 248, 265 Tepper, JS, 26, 46 Termini, R, 105, 113, 185, 205 Thach, BT, 274, 282 Theodors, A, 239, 261, 291, 292, 301 Thivolle, P, 90, 107 Thomas, D, 275, 283 Thomas, LE, 70, 78, 85 Thomas, M, 275, 284 Thomas, P, 155, 175 Thomas, PE, 241, 242, 243, 262 Thomas, VE, 103, 112 Thompson, DG, 310, 321 Thompson, JL, 89, 107 Thompson, JLP, 308, 310, 319 Thompson, RPH, 298, 302, 312, 321 Thompson, SWN, 32, 48 Thomson, AH, 247, 248, 249, 263 Thomson, HG, 90, 108 Thomson, RJ, 33, 49 Thorpe, J, 56, 60, 67 Thurston, G, 26, 46 Tibbling, L, 95, 109, 129, 130, 138, 143, 144, 148, 157, 158, 162, 165,

Author Index 166, 170, 171, 172, 173, 174, 176, 177, 178, 184, 186, 187, 188, 205, 247, 248, 256, 258, 263, 265, 267 Tileson, W, 69, 87 Tinsdale, RS, 122, 137 Toews, GB, 21, 22, 43 Togias, A, 30, 38, 47, 53 Tokiwa, Y, 248, 265 Tolia, V, 257, 267 Tomaki, M, 23, 31, 42 Tombelaine, R, 20, 40, 196, 198, 207 Tomita, T, 37, 51 Tomori, Z, 92, 108, 152, 174 Toohill, R, 69, 72, 81, 82, 83, 86, 100, 102, 111, 240, 261, 304, 319 Tooley, WH, 240, 244, 245, 246, 262, 275, 283 Torres, A, 272, 274, 280 Toscano, MS, 291, 301 Toskala, J, 239, 261, 286, 289, 291, 300 Touyz, SW, 286, 300 Tovar, JA, 105, 113 Towbin, R, 279, 284 Towner, TG, 131, 138, 165, 166, 177, 247, 263, 274, 282 Tracy, JF, 308, 320 Tran, JA, 156, 157, 158, 175, 215, 216, 234, 235, 316, 322 Treem, WR, 255, 266, 272, 281 Tremblay, J, 37, 38, 51 Tribble, CG, 26, 45 Trifan, A, 309, 310, 320 Triglia, JM, 70, 80, 86 Trudeau, WL, 165, 167, 177 Tseng, P, 286, 300 Tsicopoulos, A, 21, 43 Tsuchiya, M, 33, 50 Tsujiura, M, 33, 49 Tsukiji, J, 33, 49 Tucci, F, 189, 206 Tucci, J, 257, 267 Tuchman, DN, 95, 105, 109, 110, 152, 153, 154, 155, 158, 160, 175, 274, 282 Tuisku, T, 298, 301 Tunnell, W, 274, 283

Author Index

349

Turnage, RH, 259, 267, 279, 284 Turner, CR, 26, 33, 46, 49 Turner, CW, 122, 137 Twentyman, OP, 20, 21, 41 Tytgat, GN, 104, 112, 192, 194, 206, 257, 267

U Uejima, Y, 24, 45 Ueki, IF, 97, 110 Ulman, I, 279, 284 Umeno, E, 28, 31, 46, 47 Umetsu, DT, 21, 44 Undem, BJ, 20, 21, 22, 23, 28, 29, 30, 31, 32, 33, 34, 35, 37, 38, 39, 42, 43, 46, 47, 48, 49, 50, 53, 54 Undem, FJ, 30, 48 Underwood, DC, 38, 53 Underwood, M, 124, 137, 160, 169, 170, 175, 180, 203, 285, 300 Unge, P, 192, 206 Uray, E, 255, 266 Urbain, D, 260, 267 Urban, L, 28, 32, 47, 48 Urschel, HC, 117, 136 Utell, MJ, 90, 103, 107

V Vadas, MA, 19, 23, 40 Vaezi, MF, 98, 100, 101, 111, 286, 291, 292, 300, 301, 304, 316, 319, 322 Vakil, N, 106, 113 Valeri, CR, 24, 44, 45 Van de Rijn, M, 21, 43 Van Drunen, M, 20, 40, 196, 198, 207 Vandenplas, Y, 105, 113, 188, 205, 270, 280 Vandevenne, A, 93, 97, 98, 109, 125, 126, 137, 142, 148, 157, 158, 173, 180, 203 Vantini, I, 94, 95, 109 Vantrappen, G, 98, 99, 101, 110, 111

Varkey, B, 156, 175 Varry, M, 95, 105, 110 Velvisi, MG, 30, 34, 48 Venge, P, 20, 21, 41 Venlloch, E, 180, 197, 203 Venter, JC, 161, 176 Venugopalan, CS, 37, 38, 51 Verlinden, M, 105, 113 Viala, P, 240, 261 Vierucci, A, 189, 206, 257, 267 Vignal, J, 20, 24, 41, 170, 171, 172, 173, 178, 196, 198, 207 Vigneri, S, 105, 113, 185, 205 Viljakka, M, 229, 236 Vingerling, P, 292, 301 Vinocur, CD, 275, 283 Virchow, JC, 24, 44 Viroslav, J, 97, 110, 307, 309, 319 Vitale, GC, 78, 88, 183, 204 Voderholzer, WA, 99, 111 von Rosenstein, NR, 116, 136 Voorhees, RJ, 119, 136 Vos, M, 211, 228, 234 Voyles, JB, 275, 283

W Wagner, JI, 103, 112 Wagner, JL, 183, 204 Wagner, ML, 275, 283 Wagner, PH, 93, 109 Waki, EY, 240, 262 Walker, B, 31, 48 Walker, C, 24, 44 Walker, LH, 147, 148, 150, 162, 169, 174 Wallwork, J, 26, 45 Walner,DL, 243, 262 Walshaw, MJ, 216, 235 Wanner, J, 20, 40, 196, 198, 207 Ward, JK, 37, 51 Ward, PH, 70, 78, 86, 310, 320 Waring, JP, 168, 177, 183, 204, 274, 282, 312, 321 Washburn, LK, 93, 109

350 Wastwood, TF, 183, 204 Watanabe, N, 318, 322 Waterfall, WE, 95, 96, 105, 110 Watson, J, 33, 49 Watson, N, 28, 31, 39, 47 Weaver, AL, 304, 319 Weaver, EM, 315, 321 Weber, E, 37, 52 Weber, R, 274, 282, 317, 322 Weber, RW, 131, 138, 165, 166, 177, 247, 263 Webster, T, 162, 176 Wee, Ta, 306, 319 Weihe, E, 37, 52 Weinbech, M, 168, 177 Weinberg, H, 306, 319 Weinberger, M, 247, 265 Weiner, GJ, 56, 66, 67, 68, 96, 110, 156, 175 Weiner, T, 258, 267 Weinreich, D, 32, 33, 38, 39, 48, 49, 53, 54 Weinstock, JV, 23, 42 Weintraub, A, 93, 109 Weintraub, WH, 275, 283 Weir, T, 31, 48 Weiss, KB, 246, 263 Welbourn, R, 24, 44, 45 Welch, M, 274, 282 Welch, RW, 252, 266 Wells, GA, 162, 176 Werlin, SL, 99, 111, 244, 263, 270, 280 Wernly, JA, 161, 175 Wesley, JR, 244, 259, 263, 267, 276, 284 Wesseling, G, 144, 158, 174 Wessling, G, 248, 265 Westra, SJ, 253, 266 Wetmore, RF, 77, 87 Wetscher, G, 223, 229, 235 Wheatley, MJ, 259, 267, 276, 284 White, SJ, 244, 263 Whitehead, MW, 298, 302, 312, 321 Whittington, PF, 98, 111, 241, 262, 272, 275, 280, 283

Author Index Widdicombe, JG, 89, 92, 106, 108, 140, 152, 160, 173, 174 Wiebecke, B, 99, 111 Wiener, CJ, 69, 70, 72, 84, 85 Wiener, GJ, 69, 70, 71, 72, 80, 87, 98, 99, 111 Wilcox, CM, 83, 88 Wilde, MI, 81, 88 Wilder, B, 318, 322 Wilkinson, SP, 104, 112, 192, 193, 194, 206 Williams, H, 286, 300 Williams, JC, 26, 46 Williams, WN, 306, 319 Willing, J, 270, 280 Wills-Karp, M, 38, 53 Wilson, JW, 20, 21, 31, 41, 48 Wilson, NM, 33, 50, 247, 248, 249, 263 Wilson, RS, 186, 188, 205, 242, 262 Wilson, RSE, 125, 126, 137 Winkelstein, A, 69, 71, 87 Winter, CS, 62, 68 Winters, C, 56, 57, 60, 64, 67 Wohl, MEBG, 246, 263 Wolcott, RB, 289, 301 Wolfe, B, 253, 259, 266, 267 Wolfe, MM, 73, 87 Wolgtens, JHM, 292, 301 Wong, L, 275, 284 Woo, P, 70, 79, 86 Wood, JD, 38, 53 Wood, RD, 289, 301 Woodson, G, 310, 320 Woolcock, AJ, 19, 21, 31, 40, 43, 48, 314, 321 Working Group of the European Society of Gastroenterology and Nutrition, 252, 266 Wouters, EFM, 144, 158, 174, 248, 265 Wrannge, B, 143, 148, 157, 173, 184, 205 Wren, J, 272, 280 Wright, RA, 20, 41, 143, 145, 148, 157, 158, 173 Wu, WC, 56, 59, 67, 69, 70, 71, 72, 80,

Author Index

351

84, 85, 87, 96, 98, 99, 103, 110, 111, 112, 156, 175, 183, 204, 309, 320 Wynne, JW, 24, 44, 216, 228, 235

Yip, P, 37, 38, 51 Yoshioka, K, 26, 30, 45 Young, IG, 23, 43 Young, JL, 81, 88 Yu, XY, 30, 48

X Z Xhonga, FA, 289, 301

Y Yacoub, MH, 37, 51 Yafuso, N, 38, 52 Yamamoto, DT, 103, 112, 183, 204 Yamasaki, M, 39, 53 Yamate, M, 129, 130, 138 Yamauchi, H, 23, 31, 42 Yamawaki, I, 28, 46 Yanaihara, N, 37, 52 Yarkony, KA, 39, 54 Yazbeck, S, 224, 228, 230, 235 Yellon, RF, 318, 322 Yeomans, ND, 104, 112, 152, 174, 192, 194, 196, 206 Ying, S, 20, 21, 24, 42, 43, 44

Zaeri, W, 246, 263 Zagar, D, 308, 310, 319 Zannoli, R, 254, 266 Zawacki, JK, 20, 41, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 107, 108 Zboralske, FF, 308, 320 Zfass, A, 274, 282 Zhou, D, 31, 48 Zhu, H, 311, 313, 321 Zhu, W, 37, 52 Zillessen, E, 255, 266 Zinsmeister, AR, 56, 67, 180, 197, 203, 304, 319 Zorowitz, RD, 310, 321 Zuccali, V, 94, 95, 109 Zwi, S, 162, 176

SUBJECT INDEX

A Acid, aspiration, 135 see also Aspiration basal output, 311 citric, 28 contact time, 72, 160 (see also pH monitoring) hydrochloric, 29, 285, 289 hypersecretion, 197 laryngeal, 248 pepsin, 73 suppression, 64, 66, 67, 72, 170, 297 tracheal, 152–154, 160 Albuterol (see Pharmaceuticals) Alginic acid (see Pharmaceuticals) Alpha-adrenergic agonists (see Pharmaceuticals) Aminophylline (see Pharmaceuticals) Animal model, 21, 24–26, 28, 33–35, 37–39, 73, 74, 77, 91, 95, 97, 140, 152, 241, 243 acid-pepsin, 73, 74, 241 Angiotensin-converting enzyme inhibitors (see Pharmaceuticals) Anorexia nervosa, 285, 286

Anticholinergic agents (see Pharmaceuticals) Aspiration, 197, 215, 216, 234, 244, 273, 276, 305, 316 acid, 135 (see also Acid) antegrade, 309, 310 gastric, 20, 24, 28, 33 gross, 93 macrophage, lipid laden, 93, 154, 155, 276 microaspiration, 93, 139, 140, 145, 148, 152, 155–158, 160, 246, 273 nasopharyngeal, 307 nocturnal, 93 pneumonia, 56, 57, 215, 244, 276, 306–308, 310 retrograde, 93, 309 stroke, 307, 308, 310 tracheal, 157, 216 (see also Acid) Asthma, acute attack, 31, 162 adult, 60, 118, 119, 129, 130, 305 airway hyperresponsiveness, 21, 32– 34, 36, 38, 135, 144, 150, 152, 158, 160, 162, 180, 187, 217, 246, 248–250

353

354

Subject Index

[Asthma] airway responses, 35, 39, 273 atopic, 21, 24, 33, 39 bronchoconstriction (spasm), 20, 28– 30, 32, 33, 36, 148, 248, 273 childhood (see Children and adolescents) cough variant, 243 nocturnal, 172, 248 prevalence of association with GERD (see Prevalence) severe, 246, 305 stimulus (see Stimulus, for asthma) symptom scores, 194, 195 Atropine (see Pharmaceuticals) Attapulgite (see Pharmaceuticals) Autonomic function testing, 147

B Barrett’s esophagus, 56, 57, 60–62, 67, 81, 125, 170, 197, 211, 212, 214, 259, 260, 311 Benzocaine (see Pharmaceuticals) Bernstein Acid-Perfusion Test, 94, 95, 99, 142, 144–148, 249, 253, 276 Beta-adrenergic agonists (see Pharmaceuticals) Benzocaine (see Pharmaceuticals) Benzodiazepams (see Pharmaceuticals) Bethanecol (see Pharmaceuticals) Bile salts, 211–213 bilirubin, esophageal, 211 Bronchial, airway, infantile, 271 biopsy, 2, 21, 31, 93 bronchitis, 57, 91, 244, 245 lavage, 20, 21 Bronchiectasis, 91, 215, 234, 244, 245 Bronchiolitis obliterans, 244, 246 Bronchodilators (see Pharmaceuticals) Bronchopulmonary dysplasia, 244, 269, 272 Bulimia, 285–287, 296

C Calcium channel blockers (see Pharmaceuticals) Capsaicin (see Pharmaceuticals) Central nervous system, brainstem nuclei, 34, 92 nucleus ambiguus, 92, 140 nucleus retroambiguus, 92 nucleus of the salivary tract, 140 nucleus of the vagal nerve, dorsal, 161 developmental delay, 244 hindbrain, fish, 4 injury, neurologic, 244 level of consciousness, depressed, 244 medulla, ventrolateral, 140, 144 stroke, 307, 308, 310 aspiration pneumonia (see Aspiration) dysphasia (see Gastroesophageal reflux disease) occult, 310 Children and adolescents, 237–268 asthma, 60, 118, 119, 129–130, 237 croup, 239, 240 infants, 269–284 GERD, 272–279 nasal breathing, 271 physiology, 269–272 premature, 272 therapy, 277–279 Cimetidine (see Pharmaceuticals) Cisapride (see Pharmaceuticals) Congenital anomalies, atresia, esophageal, 244, 269 atresia, tracheal, 15 diverticulum, of trachea, 15 eventration of the diaphragm, 16 fistula, tracheoesophageal, 15, 16 hernia, diaphragmatic, 16, 269 stenosis, tracheal, 15 tracheal lobe, 16 web, laryngeal, 15

Subject Index

355

Corticosteroids (see Pharmaceuticals) Cough, chronic, 56, 58, 61, 63, 64, 70, 72, 74–76, 89–113, 189, 214, 239, 243, 305, 311 asthma (see Asthma) awake, 97 bronchiectasis (see Bronchiectasis) bronchitis (see Bronchial) gastroesophageal reflux (see Gastroesophageal reflux) multiple, 91, 92 postnasal drip (see Allergic rhinitis) duration, 97 nocturnal, 92 relationship to reflux, temporal, 96 sputum, 97 threshold, 94 upright, 97 Cystic fibrosis, 79, 269 Cytochrome p450 (see Pharmaceuticals)

D Dental erosions, 56, 98, 285–302 acid-induced, 285 (see also Acid) dietary, 288 industrial, 288 classification, 287, 288, 290 diagnosis, differential, 292–296 enamel, 291 etiology, 288, 289 reflux, gastric acid (see Acid) vomiting, chronic, 289 hypersensitivity, dentinal, 286, 287 prevention, 297–298 mouth guard, 298 treatment, 298, 299 dental restoration, 299 Diagnostic evaluation of GERD, 55–88, 121–125, 250, 315 barium studies, 57–60, 66, 74, 79– 81, 92, 93, 98, 252, 308 bolus, solid, 60 hiatal hernia (see Hiatal hernia)

[Diagnostic evaluation of GERD] rings, 59, 81 webs, 59 Bernstein test (see Bernstein acidperfusion test) biopsy, esophageal, 58, 61, 62, 74, 92, 253, 277, 291, 316 bronchoscopy, 275, 276 endoscopy, 57, 58, 61, 62, 66, 67, 69, 72–81, 92, 93, 99, 120, 201, 312 history, 250 laryngoscopy, 61, 66, 70–81, 251, 275, 305, 310, 317 manometry, esophageal, 57, 58, 62, 65, 73, 74, 78, 79, 92, 95, 96, 139, 160–169, 171, 201, 217– 222, 232–234, 252, 308, 309 preoperative, 65, 217–222, 232– 234 sphincter, lower (LES), 57, 62, 65, 73, 78, 82, 139, 160, 161, 163, 165–169, 183, 187, 197, 209, 211–213, 247, 270, 309 sphincter upper (UES), 73, 74, 79, 238, 270, 308, 309 methylene blue, 276 nasopharyngoscopy (see rhinopharyngoscopy) pH monitoring, 57, 58, 61–64, 66, 67, 71, 92, 97, 99, 100, 145– 160, 166, 167, 181, 186–188, 192, 196, 201, 215, 217, 218, 240, 243, 249, 252, 253, 257, 275, 276, 304, 311, 316, 317 ambulatory, 62, 99 distal, 63, 64, 172 dual, 64, 66, 80, 81, 84, 94, 99, 145–156, 171, 172, 216, 233, 252, 291, 304, 316, 317 hypopharyngeal, 63, 80, 81 intragastric, 63 nasopharyngeal, 241 proximal, 63, 64, 156, 172, 173, 196, 216

356

Subject Index

[Diagnostic evaluation of GERD] tracheal, 154–157 (see also Aspiration) values, normal, 63 rhinopharyngoscopy, 251, 305 scintigraphy, 93, 154, 155, 251, 252, 275, 316 Tuttle test, 253 ultrasonography, 253, 254 x-ray, chest, 90 Diaphragm, 10–12 central tendon, 12 crural, 139, 163–165 eventration (see Congenital anomalies) hernia (see Congenital anomalies) Diazepam (see Pharmaceuticals) Diphenhydramine (see Pharmaceuticals) Domperidone (see Pharmaceuticals) Dopamine (see Pharmaceuticals) Dyclonine (see Pharmaceuticals)

E Epiglottis, 5–7 Epinepherine (see Pharmaceuticals) Esophageal acid clearance, 58, 73, 74, 79, 80, 95, 96, 147, 189, 210, 214 factors, activity, motor, 210 anchoring of distal esophagus, 210 gravity, 210 salivation, 210 (see also Saliva) ineffective, 210 Esophagus, 4, 7, 13, 14 distention, 95, 142 epithelial glands, 14 esophagitis, 57, 60, 61, 72, 73, 93, 125, 148, 153, 170–172, 181, 185–189, 193, 194, 211–215, 248, 311, 316 infantile, 270 injury, progressive, 211 length, 161, 197, 219

[Esophagus] malignancy, 57, 62, 81, 99, 214 presbyesophagus, 308, 309 short, 209, 220, 224, 238 stricture, peptic, 56, 57, 59, 79, 81, 98, 197, 211, 214, 220, 260, 316 ulceration, 57, 98, 125

F Famotidine (see Pharmaceuticals) Fenoterol (see Pharmaceuticals) Fish, 2–4 lung fish, 4, 7 swim bladder, 3 Foregut, embryonic, 2, 13, 15

G Ganglionic blocker (see Pharmaceuticals) Gastroesophageal reflux disease (GERD), 25, 55, 90–92, 213, 309 asthma, as a cause, 247, 248 complications, 56 bleeding, 56 esophagitis, 57, 60, 61, 72, 73, 93 stricture, 56, 57, 59, 79, 81 ulceration, 57, 98, 125 diagnosis (see Diagnostic evaluation of GERD) medical therapy, 179–207 occult, 97, 181, 202, 215, 238, 304 physical findings, erythema, pharyngeal, 251 headcocking (see Sandifer’s syndrome) reflux, acid (see Acid) alkaline, 95 bipositional, 212, 213, 304 daytime, 72, 73

Subject Index [Gastroesophageal reflux disease (GERD)] duodenal, 211 duration, 96 frequency, 64 gastroduodenal, 212 laryngitis, 58, 59, 70, 74, 81, 84, 100, 215, 239, 240, 305, 310 nasal, 269, 274 nocturnal, 73, 80, 183 number of episodes, 96 pathologic, 73, 96, 311 pharyngeal, 74, 238, 243, 270, 274, 285, 309 physiologic, 73, 96, 237 postprandial, 96 provoked by treatment, 274 response to therapy, 66 supine, 64, 72–74, 80, 83, 212, 213, 304 symptom score, 172 trypsin, 95 upright, 64, 72–74, 80, 83, 96, 212, 213, 304 voluntary, 285 risk factors, 211 silent, 97, 181, 202, 215, 238, 304 spectrum, 55–57 symptoms, 56, 238 anemia, 61, 260, 305 apnea, infantile, 215, 269, 271, 272, 274, 275 aspiration pneumonia (see Aspiration) asthma (see Asthma) belching, 251, 305 bleeding, 61, 260 bronchitis (see Bronchial) cervical pain, 305 chest pain 56, 61, 63, 98, 214, 305 choking, 72, 214 cough, chronic (see Cough) crying, intractable in infant, 273 drip, postnasal, 70 dysparunia, 56 dyspepsia, 56

357 [Gastroesophageal reflux disease (GERD)] dysphagia, 59, 61, 70, 75, 76, 79, 84, 160, 251, 308 dysphonia, 70, 75, 76, 84 erosion, dental (see Dental erosions) globus, 56, 70, 72, 74–76, 79, 84, 98, 239, 242 heartburn, 55, 57–60, 74, 97, 117, 145, 179, 181, 187, 251, 260, 305 hiccups, 36, 305 hoarseness, 56, 57, 61, 72, 74, 98, 215, 239, 240, 305 mouth burning, 286, 298 mouth dry, 286 mucous, excessive throat, 70 night sweats, 56 odynophagia, 61 otalgia, 56, 241 postural worsening, 117 questionnaire, 304, 317 regurgitation, 55–57, 97, 145, 160, 172, 173, 179, 181, 187, 196, 214, 305 sore throat, 72, 79, 98, 242, 305 stridor, 98, 240, 269, 272, 275 taste, sour, 98 teeth, sensitive (see Dental erosions) throat clearing, chronic, 70, 72, 75, 76, 84, 214, 239, 242 tongue, sensitive, 286 ulcers, oral, 56, 286, 298 voice fatigue, 70 waterbrash, 97, 251 weight loss, 61 Geriatric, 304–313 anatomic, 306, 307 lactose intolerance, 312 reflex changes (see Reflex, geriatric changes) sicca syndrome, 312 sensory changes, 306 airways, upper, 306

358

Subject Index

[Geriatric] lip, 306 pharynx, 306, 307 proprioceptive, 306 stereognostic, 306 supraglottic, 306, 307 temperature, 306 tongue, 306 two point, 306 Glottis, 5

[Inflammation] neurogenic, 24–54, 158, 160 neuronal activation, 25 proinflammatory neurotransmitters, 26 pulmonary, 26 skin, human, 30, 31 upper airway, human, 30 vasodilation, 20, 27 Ipatropium bromide (see Pharmaceuticals) Isoproterenol (see Pharmaceuticals)

H L hexamethonium (see Pharmaceuticals) H2-receptor antagonists (see Pharmaceuticals) Hiatal hernia, 59, 98, 117, 125, 127– 130, 161, 197, 210, 220, 253, 274, 311 incidence, 163 large, 65 paraesophageal, 220 sliding, 220 Histamine challenge (see Asthma, airway hyperresponsiveness)

I Immunoglobulin E, 246 Inflammation, 19–54, 89, 180, 306, 315 cells, basophils, 21–24 endothelial, 33 eosinophils, 20–23 epithelial, 20, 22, 23, 26, 33 hyperalgesia, 31, 32 macrophages, 21, 22 (see also Aspiration) mast cells, 21, 22, 24, 33 mononuclear, 20 neutrophil, 24 mediators (see Mediators of inflammation) mucosal edema, 20

Lansoprazole (see Pharmaceuticals) Laryngopharyngeal reflux, 69–88, 228, 248 arytenoid fixation, 70, 76 carcinoma, 70, 75, 76, 78, 83 degeneration, polypoid, 70, 75–77 dysplasia, 76 edema, laryngeal, 70, 71 esophagitis, differences, 69 globus, 56, 70, 72, 74–76, 79, 84, 98, 239, 242 hematoma, 76 injury, endotracheal tube, 70 laryngomalacia, 70, 239, 240, 271, 275 laryngospasm, paroxysmal, 70, 75– 77, 240, 241, 273 leukoplakia, 70, 76, 78 nodules, vocal, 70, 75, 76 pachydermia, laryngitis, 70, 76 pediatric, 80, 237–243 Reinke’s edema, 75–77 stenosis, posterior glottic, 70, 239, 243 stenosis, subglottic, 70, 71, 75, 76, 78, 83, 239, 242, 243 ulcers and granulomas, contact, 70, 76, 77, 117, 239 voice disorders (see Voice disorders) Larynx, 2, 7, 315 aryepiglottic folds, 7

Subject Index [Larynx] arytenoid, 7–8 cricoid, 8 infantile, 271 laryngotracheal bud, 8 ventricles, 7 Lidocaine, viscous (see Pharmaceuticals) Lifestyle, alcohol, 78, 183 chocolate, 183 drugs, 183 food, fatty, 183 infantile, 271 volume, 238, 271 infantile, 271–272, 277, 278 modifications, 71, 81, 83, 103, 116, 171, 181–184, 200–201, 210, 214, 238, 254, 255, 314 obesity, 183, 238 sleep time, 238 tobacco, 78, 89 Lignocaine (see Pharmaceuticals) Lung, abscess, 244, 245 alveolar pneumocyte, 10 amphibian, 4 avian, 4 bronchi, 8 development, 9–10 granulomatous pneumonia, recurrent, 244, 245 lobes, 5 tracheal (see Congenital anomalies) mammalian, 4 parenchyma, 4 pleura, 9 pulmonary artery, 12 pulmonary fibrosis, 215, 234, 244, 246, 305, 313 reptile, 4 segments, 4 surfactant, 10 Lymphocytes, CD, 4, 21

359 [Lymphocytes] murine Th, 21, 23 Th 1, 21 Th 2, 21 T helper, 21

M Mediators of inflammation, autocoids, 20–24, 33 bradykinin, 22, 26–28, 33, 36, 37 cysteinyl-leukotrienes, 22, 24 cytokines, 21, 24, 33, 38 endothelins, 22, 33, 36, 37 histamine, 22, 24, 26 IL-1, 22 IL-2, 21 IL-4, 21, 23, 24 IL-5, 23 IL-8, 23–25, 33, 36, 37 IL-13, 21, 24 interferon-gamma, 21 major basic protein, 22 MIP-1 alpha, 24 neurokinin A, 26, 27, 30 neuropeptides, 26 RANTES, 23 substance P, 26, 27, 30, 34, 37 tachykinins, 22, 26, 30, 31, 36, 37, 39 TNF-alpha, 24 Meperidine (see Pharmaceuticals) Methylanthines (see Pharmaceuticals) Metoclopramide (see Pharmaceuticals) Morphine (see Pharmaceuticals)

N Neurotransmitters, 32 acetylcholine, 35, 36, 37, 39 autonomic, 38 calcitonin gene-related peptide (CGRP), 37

360

Subject Index

[Neurotransmitters] cytokines (see Mediators of inflammation) galanin, 37 neuropeptide Y, 37 NO, 36, 37 noradrenaline, 35 relaxant type, 36 substance P (see Mediators of inflammation) tachykinins (see Mediators of inflammation) VIP, 36, 37, 38 Nizatidine (see Pharmaceuticals)

O Office approach, 317, 318 Omeprazole (see Pharmaceuticals) Oral manifestations of GERD, 285–302 dental erosions (see Dental erosions) eating disorders, 285 (see also Anorexia nervosa; Bulimia) mucosal lesions, 286 periodontal, 286 salivary gland, 286, 287 (see also Saliva) Otitis media, 237, 239, 241, 242

P Pantoprazole (see Pharmaceuticals) Peripheral nervous system, 22 airway adrenergic, 25, 26 airway afferents, 31–33 airway ganglia, 35 autonomic, 25, 38 capsaicin, desensitization, 26, 36, 37 cholinergic, 34–38, 161 dysfunction, 161 esophageal myenteric plexus, 34, 35 ganglion neurons, 31 myelinated fibers, 307

[Peripheral nervous system] nociceptive afferent, 27 NANC, 13, 36, 37, 38 (nonadrenergic noncholinergic) parasympathetic, 13, 161 parasympathetic, adrenergic, 34, 35 parasympathetic cholinergic, 34, 35, 37–39 parasympathetic ganglion, 28, 34, 36, 37, 39 parasympathetic postganglionic, 38 peripheral efferent, 36 phrenic nerve, 10–12, 34 recurrent laryngeal nerve, 12 retrograde tracing studies, 34 sympathetic, 12, 34, 35, 38 tachykinin-containing fibers, 39 vagus nerve, 2, 4, 8, 12–15, 36, 38, 140 efferent, 36 inferior laryngeal, 8 superior laryngeal, 12, 77, 306, 307 visceral afferent, 27 Pharmaceuticals, albuterol, 168 alginic acid, 181–184, 256, 278, 314 alpha-adrenergic agonists, 183 aminophylline, 165 angiotensin-converting enzyme inhibitors, 90 anticholinergic agents, 169 atropine, 143, 147, 148, 151, 152, 158 attapulgite, 299 benzocaine, 299 benzodiazepams, 185 beta-adrenergic agonists, 19, 161, 183, 184, 187, 247 bethanecol, 187, 257 bronchodilators, 131–134, 306 (see also beta-adrenergic agonists, aminophylline, methylxanthines, theophylline) calcium channel blockers, 183 capsaicin, 26, 29, 30, 33, 95 cimetidine, 170, 182, 185–189, 197,

Subject Index [Pharmaceuticals] 256 (see also H2-receptor antogonists) cisapride, 104, 105, 187–190, 257, 278, 312–314, 318 (see also prokinetic agents) corticosteroids, 19–21, 168, 169, 180, 192, 193, 196, 317 cost (see Therapeutic trial) cytochrome p450, 312 diazepam, 183 diphenhydramine, 299 domperidone, 182, 187, 257 dopamine, 183 dyclonine, 299 epinepherine, 167 famotidine, 182, 185, 256, 278, 313 (see also H2-receptor antagonists) femoterol, 168 (see also beta-adrenergic agonists, bronchodilators) ganglionic blocker, 38 hexamethonium, 38 H2-receptor antagonists, 58, 61, 74, 80, 81, 83, 103–105, 181, 182, 185–189, 202, 256, 313 ipatropium bromide, 33, 94, 192 isoproterenol, 167 lansoprazole, 66, 81, 182, 190, 192, 256, 257, 313, 314 lidocaine, viscous, 299 lignocaine, 94 meperidine, 183 methylxanthines, 247 metoclopramide, 104, 187, 257, 278, 312 morphine, 183 nizatidine, 182, 185, 313 omeprazole, 66, 81, 83, 84, 104, 105, 170–172, 256, 257, 278, 298, 312–314 orabase, 299 pantoprazole, 182 phytoin, 185 pilocarpine, 298 prednisone, 168

361 [Pharmaceuticals] progesterone, 183 prokinetic agents, 58, 61, 103–105, 181, 257, 277, 318 prostaglandins, 183 proton pump inhibitors, 58–61, 66, 74, 77, 78, 80–85, 104, 105, 190–197, 210, 214, 215, 256, 312, 317, 318 ranitidine, 105, 171–182, 185–189, 192, 200, 256, 278, 313, 314 sucralfate, 258, 278, 313, 314 theophylline, 161, 165–169, 183, 196, 247, 305 warfarin, 185 zilactingel, 299 Pregnancy, 184, 185, 187, 314 Prevalence, 56–57, 69 cough, 98, 316 gastroesophageal reflux, 56, 316, 317 in asthma, 115–138, 180, 237, 316, 317 incidence, 121–122 laryngopharyngeal (LPR), 69, 84, 316, 317 pulmonary disease, 316–317 tooth erosions, 289 Progesterone (see Pharmaceuticals) Progressive systemic sclerosis, 93 Prokinetic agents (see Pharmaceuticals) Prostaglandins (see Pharmaceuticals) Proton pump inhibitors (see Pharmaceuticals) Pulmonary function tests, airway resistance, 95, 142, 145–147, 153, 154, 158, 249 capsaicin inhalation challenge, 95 closing volume, 143 compliance, dynamic, 153 cough threshold, 95 flow volume loop, 317 FEV, 95, 181, 186–189, 193, 200 FVC, 95, 143, 186 histamine challenge (see Asthma, airway hyperresponsiveness) hyperventilation, isocapnic, 150

362

Subject Index

[Pulmonary function tests] impedance, 144 inductance, 249 methacholine challenge, 94, 95, 120, 150, 151, 158, 161, 162, 188 oxygen saturation, 143 peak expiratory flow, 144–147, 158, 181, 187–189, 195, 200, 202, 249 pressure pleural, 153, 162, 169, 243, 247 restrictive changes, 305 slope of alveolar plateau, 143 spirometry, 144–147

R Ranitidine (see Pharmaceuticals) Receptors, acid sensitive, 170 afferent esophageal, 92 cholinergic, prejunctional, 36 cough, 92 rapidly adapting irritant, 92 muscarinic, M2, 36, 37, 39 M3, 30 receptor antagonist, 33 NK1, 39 NK1 antagonist, 30 NK 3, 39 tachykinin, 30, 31 preprotachykinin gene, 33 receptor antagonist, 33, 34 Reflex, autonomic, 32 axon, 26–28, 31 esophagus and trachea, 28 bronchoconstriction, 20 central, 27 defensive, 26 esophagobronchial cardiac, 143, 246 esophagoglottal closure, 93, 307, 309

[Reflex] geriatric changes, 307, 308 inappropriate, 32 inflammation, 26 involuntary cough, 92 peripheral, 34 parasympathetic, cholinergic, 33, 34, 143 pharyngoglottal, 93, 310 respiratory, 10 tracheobronchial cough, 92 tracheobronchial–esophageal, 92, 94, 95 vagal, 84, 85, 92, 97, 139–141, 147, 152, 170, 173, 241, 246, 273 centrally mediated, 34 Rhinitis, allergic seasonal, 33 chronic, 239, 241 postnasal drip, 90–92 rhinopharyngitis, 241

S Saliva, artificial, 298 buffering capacity, 291, 298 flow, 291, 292, 298 gum, sugar free, 298 mucin levels, 292 salivary glands (see Oral manifestations) sicca syndrome, 312 xerostomia, 79 Sandifer’s syndrome, 251 Sinusitis, 239, 305 Sjogren’s syndrome, 79 Sleep, apnea, 162 nasal CPAP, 162 peristalsis, esophageal, 183 saliva, decrease, 183 upper esophageal sphincter (UES)

Subject Index Stimulus for asthma, acid exposure time, 28, 211 (see also Acid) allergen, 28 bradykinin (see Mediators) heartburn, 28 (see also Gastroesophageal reflux disease) hyperpnea, 28 meals, 305 ozone, 39 positional changes, 305 saline, hypertoic, 28 smoke, cigarette, 28 viral infection, 39 Stomach (gastric), 15 emptying, 187, 210 delayed, 161, 197 distention gastric, 161, 210 compliance, 270 pain, 305 parietal cell, 190, 191 receptors, 190, 191 volume ratio, to esophagus, 270 Sucralfate (see Pharmaceuticals) Sudden infant death syndrome, 77 Surgery, 27, 60, 65, 67, 78, 80, 103, 105, 106, 117, 182, 196–201, 209–236, 278, 279, 313 algorithm, 217, 219, 221, 231 angelchik prosthesis, 259 Belsey fundoplication, 105, 220, 222, 224, 229–232, 259 Borema anterior gastropexy, 259 compared to medical therapy, 197– 200, 223 Collis gastroplasty, 224–226, 231, 232 complications, 225–228, 258, 259 chest pain, 226 dysphagia, 225–227 gas bloat syndrome, 226, 228 gastroparesis, 226 herniation of repair, 226 recurrent reflux, 226–228, 259 vagal nerve injury, 226 crural closure, 228

363 [Surgery] esophageal lengthening precedure, 220, 222, 225 fundoplication, 78, 80, 82, 83, 90, 171, 197–200, 223, 224, 233, 278, 279 redo, 226 gastric antrostomy, 259 gastrojejunostomy, 278, 279 Hill posterior gastropexy, 105, 170, 197–199, 225, 259 indications, 217 intractable symptoms, 259 laparoscopic, 222–229, 258, 259, 279, 313, 318 laryngeal, 84 Nissen fundoplication, 65, 105, 106, 171, 198–200, 220, 222, 229– 231, 258–260 proper procedure, 219 pyloroplasty, 259 results, 232, 233 risks, 197 short esophagus (see Esophagus) Thal procedure, 259 Toupet procedure, 65, 222, 224, 226 tracheotomy, 82 transthoracic, 220, 222, 231 vagotomy, 27, 95, 140, 142, 153, 154, 158, 160 Swallowing, 308–310 laryngopharyngeal sensory test, 308 primary, 309 reflex changes, 307, 308 videoendoscopy, 308 videofluoroscopy, 308, 310

T Theophylline (see Pharmaceuticals) Theraputic trial, 58, 59, 64, 66, 98, 102, 180, 275 cost, 180, 254, 312, 313, 317 maintenance, 180 Tongue (see Geriatric)

364

Subject Index V

Vocal cord dysfunction syndrome, 317 Vocal cords, 4, 7 false, 5, 7 Voice disorders, 69–104, 305, 310 breaks, 70 dysphonia, 70, 75, 76, 84 fatigue, voice, 70

[Voice disorders] singer, 76 speaker, 76 symptoms (see Symptoms)

Z Zilactingel (see Pharmaceuticals)